To evaluate the safety and tolerability of FFP104 in PBC subjects following repeat doses of FFP104
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
This is an exploratory study to evaluate the safety and tolerability,
pharmacokinetics and efficacy of FFP104. The general strategy of the
analysis will be to examine the data summaries for any trends amongst the dose
levels. No formal hypothesis testing will be conducted.
Exploratory comparisons between dose cohorts can be performed, using
non-parametrical statistical methods.
Secondary outcome
• Proportion of subjects with a 10% decrease in ALP from baseline values at 12
weeks after Day 0 (first dose of FFP104)
• Proportion with a 25% and 40% decrease in ALP at Week 4, 8, 12 after Day 0
• Proportion with ALP < 1.67 from upper level of normal (ULN), an ALP decrease
>15% and bilirubin within normal levels at Week 4, 8, 12 and 24 week 4, 8, 12
and 24 after Day 0
• Proportion of subjects with a biochemical response according to 'Paris I'
criteria: ALP <= 3x ULN and AST <=2 x ULN and bilirubin <=1mg/dL at Week 4, 8, 12
and 24 after Day 0
• To evaluate the individual and mean changes in serum ALP, ALT, AST,
bilirubin, albumin, and GGT over time (evaluation of individual and mean
changes in lab values over time from baseline values) after Day 0 at Weeks 2,
4, 6, 8, 12, 16 and 24
• To evaluate changes from baseline with Mayo Risk Score at 4, 8, 12 and 24
weeks
• To evaluate changes from baseline in the Patient Report Outcome PBC-40
Quality of Life at 12 and 24 weeks
• To evaluate changes from baseline in pruritus using the Visual Analog Scale
(VAS) at 12 and 24 weeks
• To evaluate changes in PK over time from baseline
Background summary
Primary biliary cirrhosis (PBC) is an organ specific autoimmune disease
characterized by specific loss of tolerance to an ubiquitous mitochondrial
antigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2). The
functions of CD40 in immune regulation suggest that CD40-CD154 interactions
may play a role in diseases where anomalous immune responses are a feature,
e.g. autoantibody production or chronic inflammation. The CD40-CD154 (CD40L)
co-stimulatory pathway has been validated in animal models as a promising
clinical target for treatment of autoimmune
disease. In a new murine model of autoimmune cholangitis, antiCD40L antibody
reduced liver inflammation and AMA antibodies through 12 weeks of treatment.
The investigationalmedicinal product, FFP104 is a deimmunized version of a
previously investigated chimeric monoclonal antibody (ch5D12) that specifically
targets human CD40.There are good indications that the proposed medicinal
product, FFP104, will have beneficial effects on two
crucial pathogenic mechanisms in PBC: 1) chronic inflammation, and 2) apoptosis
of biliary epithelial cells.
Study objective
To evaluate the safety and tolerability of FFP104 in PBC subjects following
repeat doses of FFP104
Study design
This study is a phase I/II, open label, multicenter, pilot dose escalating
study
Intervention
The study consists of four (4) dosing cohorts of 6 subjects each to be dosed
with FFP104 as assigned. Each Cohort will have an A& B part with 3 subjects
each.
The 4 dosing cohorts are defined as follows:
1) 1.0 mg/kg FFP104 administered once weekly for 12 weeks (total exposure 12
mg/kg after 12 weeks)
2) 2.5 mg/kg FFP104 administered once weekly for 12 weeks (total exposure 30
mg/kg after 12 weeks)
3) 5.0 mg/kg FFP104 administered once weekly for 12 weeks (total exposure 60
mg/kg after 12 weeks)
4) 5.0 mg/kg FFP104 administered once every second week for 12 weeks (total
exposure 30 mg/kg after 12 weeks)
In the first cohort, after the first subject has had two (2) doses of FFP104
and has shown the dosing is safe and tolerated and with approval from the PI,
and MM review of the data, the next subject may be enrolled and dosed for two
doses before confirming that the third subject can be enrolled. After the
second and third subjects in the first cohort have had two (2) doses of FFP104
and have shown the dosing is safe and tolerated, and with review and approval
of the data from the PI and review by MM, the next three subjects in that
cohort (Part B) may be enrolled.
For subsequent cohorts, in order for the dosing to be initiated into the next
higher dosing cohort, at least three subjects in the preceding dose cohort will
have received 4 weeks of dosing. At that time the safety and tolerability
assessments for treated subjects will be reviewed and approved by the PI,
Sponsor supported by MM and DSMB. After the second and third subjects in the
Part A of the cohort have had two (2) doses of FFP104 and have shown the dosing
is safe and tolerated as defined above and with review and approval of the data
from the PI and reviewed by MM, the
next three subjects in that cohort (Part B) may be enrolled. All three subjects
in the Part A of a cohort must be dosed at least two (2) times before the PI,
Sponsor and MM provide approval to enrolling subjects in the Part B of a cohort.
Dose escalation decisions are based on the assessments of safety and
tolerability with review of overall safety by the PI, Sponsor supported by MM
and DSMB. The sites will then be informed that they may enroll subjects to be
included in the next dosing cohort.
Study burden and risks
Currently human data is limited for FFP104 which is from Phase I/II clinical
studies in patients with Psoriatric Arthritis and Crohn's disease.
At this moment a study is ongoing in healthy volunteers to evaluate safety,
tolerability and pharmacokinetic and pharmacodynamic changes. This will be the
first clinical study to evaluate FFP104 in subjects with PBC where it is to be
expected to have beneficial effects on two crucial pathogenic mechanisms in
PBC: 1) chronic inflammation, and 2) apoptosis of biliary epithelial cells
By testing 3 different multiple dose levels of FFP104, this trial will be used
to guide therapeutic dose selection for future studies.
Subjects wil receive various dosages of FFP104 over a period of 12 weeks and
will be followed for an additional 12 weeks in order to allow sufficient safety
data to be collected based on the pharmacokinetic profile of FFP104, given its
anticipated half-life.
Safety and PD assessments have been selected to monitor subjects based on the
current understanding of the mechanism of action of FFP104.
To be able to collect this information the trial subjects will visit the
hospital 17 times over a period of 24 weeks. These visits vary in length from 1
to 5 hours, depending on study drug infusions and other procedures to be done.
No immediate therapeutic effect is to be expected in this dosing finding study,
however there are findings from studies in mice and tissue research that the
drug may have a positive effect on PBC and the diseased bile ducts. This said,
the drug is experimental and has never been administered in patients with PBC.
This study is performed to investigate whether the drug is safe and may have a
positive effect on PBC. For the future, the study may also provide useful
information for the treatment of patients with PBC or other autoimmune
disorders.
Due to the fact that that participating in this trial is very time consuming
for subjects, both in number of visits as well as in length of some visits,
subjects will be compensated for their time to a maximum of 900 euros
(depending on number of visits completed).
Although data is limited, it is known that >90% of all subjects in previous
clinical trials experienced some form of treatment emergent adverse events
(AEs) that were mild to moderate in intensity. Only 12% (6/47) of the subjects
experienced severe AEs. There were no deaths in any of the studies.
The most commonly occurring AEs were abnormal laboratory values with increase
in transaminases / hepatic enzymes. Some subjects experienced severe headeach,
dizziness, muscle pain or fever. In addition it is possible to develop an
allergic reaction to the study medication which could include itching, rashes
and/or difficulty in breathing.
Yalelaan 46
Utrecht 3584 CM
NL
Yalelaan 46
Utrecht 3584 CM
NL
Listed location countries
Age
Inclusion criteria
1) Willing and able to provide signed written informed consent to participate in the study.
2) Willing and able to comply with all study procedures and scheduled visits.
3) Male or Female Age between 18 and 75 years of age inclusive at the time of signing the informed consent.
4) Established diagnosis of PBC according to the EASL criteria (European Association for the Study of the Liver 2009): A diagnosis of PBC can be made with confidence in adult patients with otherwise unexplained elevation of ALP and presence of AMA (>=1:40), and/or AMA type M2. A liver biopsy is not essential for the diagnosis of PBC in these patients, but allows activity and stage of the disease to be assessed.
5) Having a screening ALP serum level between 1.67 and 5 x ULN inclusive.
6) Be on a stable dose of UDCA 12-20 mg/kg/day for at least 3 months prior to screening or intolerant of UDCA in the opinion of the investigator (no UDCA for at least 8 weeks prior to screening).
7) Are not pregnant or breast feeding and do not plan to become pregnant or father a child during the study. Female subjects (of childbearing potential) must be willing to use two medically accepted forms of contraception throughout the study and must be willing to submit to pregnancy test(s). Male subjects must agree to use medically accepted contraception methods with their partners throughout the study as described above, unless they have had a prior vasectomy.
8) Has the ability to communicate adequately with the study staff and to comply with the requirements of the entire study, with the help of a caregiver, if applicable.
Exclusion criteria
1) Laboratory screening results
a) ALT >5x ULN
b) AST >5x ULN
c) Total bilirubin >2x ULN. Isolated bilirubin >2xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%
d) Total WBC <3000 cells/mm3
e) Absolute neutrophil count (ANC) <1500 cells/mm3
f) Platelet count <100,000/mm3
g) Prothrombin time (international normalized ratio (INR) >1.2
2) BMI >=35 or suspected to have relevant nonalcoholic fatty liver disease (NAFLD) as based on the judgment of the Investigator at screening
3) Subject has a history of, or current viral hepatitis B or C (including hepatitis B surface antigen [HBsAg], hepatitis B core antibody and hepatitis C virus antibody [anti-HCV] positivity), or a positive HIV antibody screen at time of screening
4) Recipients of liver or other organ transplantation or anticipated need for orthotropic organ transplantation in one year as determined by the Mayo Risk Score
5) Co-existing liver or biliary diseases, such as primary sclerosing cholangitis, choledocholithiasis, acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis (NASH), acute infection of bile duct system or gall bladder, history of gastrointestinal bleeding (secondary to portal hypertension), cholangiocarcinoma diagnosed or suspected liver cancers
6) Recurrent variceal hemorrhage, uncontrolled encephalopathy, Child-Pugh Class B/C, Esophageal Varices, or refractory ascites within the previous 6 months of screening (defined as date informed consent signed)
7) Have a family history (more than one first degree relative) of multiple thrombotic events or a personal history of any venous or arterial thrombotic event including deep vein thrombosis, stroke, myocardial infarction, pulmonary embolus, or peripheral arterial thromboembolic events
8) Prohibited medications 6 months prior to screening: azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; fenofibrate or other fibrates; budesonide and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazid, or nitrofurantoin)
9) Prohibited medications 12 months prior to screening: antibodies or immunotherapy directed against interleukins or other cytokines or chemokines
10) Subjects with recurrent bacterial infections (as judged by the investigator) within 6 months prior to screening, active bacterial, fungal or mycobacterial infections observed during screening, or any recent episode of infection requiring hospitalizations or treatment with antibiotics (within the 3 months prior to screening)
11) History of malignancy, with the exception of resected basal cell carcinoma, squamous cell carcinoma of the skin, or resected cervical atypia or carcinoma in situ
12) Immunization with a live vaccine within 4 weeks of Screening, with the exception of influenza vaccine and no planned immunizations within the period of the study.
13) Known clinically significant cardiac disease (e.g., myocardial infarction or stroke, unstable angina, claudication, etc.), or evidence of a clinically significant electrocardiogram (ECG) abnormality within the previous 12 months prior to screening.
14) Subjects with evidence of other serious, significant, acute or chronic medical or psychiatric illness that, in the judgment of the Investigator, could compromise subject safety, limit the subject's ability to complete the study, and/or compromise the objectives of the study
15) History of recent (within 12 months of screening) alcohol or drug abuse or non-adherence with treatment or other experimental protocols
16) Use of other immunosuppressive medications 4 weeks prior to screening
17) Active tuberculosis (TB) in the past or currently, suspected TB which is presently receiving treatment or prophylactic therapy, has a positive TB test (as defined by local biological requirements), or any significant abnormality on chest X-ray within 3 months prior to screening
18) Subjects who have planned surgery during the study period or have undergone major surgery within the 3 months prior to Screening
19) Known clinically significant allergy or known hypersensitivity to drugs that, in the opinion of the Investigator, may affect the patient's safety
20) Known sensitivity to any component of the study drug or previous sensitivity reaction or other clinically significant reaction to intravenous medications or biologic therapy
21) Participated to another clinical trial within past 30 days prior to screening or is still within a washout period of a previous clinical trial or has previously received FFP104 (PG102) or ch5D12 in this or any study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001638-27-NL |
| ClinicalTrials.gov | NCT02193360 |
| CCMO | NL49733.078.14 |