The primary objective of this study is:• To evaluate whether simtuzumab (formally referred to as GS-6624) is effective at preventing the progression of liver fibrosis in subjects with PSC.The secondary objectives of this study include the following…
ID
Source
Brief title
Condition
- Bile duct disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is:
- to evaluate whether simtuzumab is effective at preventing the progression of
liver fibrosis in subjects with PSC.
The secondary objective is:
- to compare multiple tools used for the assessment of efficacy in this
population. To meet these ends, multiple efficacy endpoints will be assessed.
For each assessment each simtuzumab dosing group will be compared to the
placebo group.
The primary endpoint will be change from Baseline in morphometric quantitative
collagen on liver biopsy at week 96.
Secondary outcome
Exploratory endpoints will include:
• Change from baseline in morphometric quantitative collagen on liver biopsy at
week 48;
• Prevention of progression of PSC as assessed by change from Baseline in the
Mayo Risk Score;
• Prevention of progression of liver disease as assessed by change from
Baseline in the MELD score;
• Assess the rate of events related to progression of PSC in each treatment
arm, including variceal bleeding, ascites, encephalopathy, ascending
cholangitis, cholangiocarcinoma, hepatocellular carcinoma, transplant and death.
• Improvement in liver biochemistry as assessed by change from Baseline in
serum alkaline phosphatase levels;
• Change from Baseline in the Ishak fibrosis stage on liver biopsy;
• Reduction in the proportion of activated hepatic stellate cells as assessed
by change from Baseline in α-smooth muscle actin
on liver biopsy;
• Change from Baseline on a VAS assessment of pruritus severity;
• Prevention of the development of new strictures or worsening strictures as
assessed by end of treatment MRCP as compared to Baseline;
• Reduction in fibrosis disease activity as assessed by change from Baseline in
serum LOXL2 levels;
• Change from Baseline in non-invasive markers of fibrosis including the ELF*
test and FibroTest/FibroSURE tests.
• Reduction in liver fibrosis as assessed by change from Baseline MRE in the
MRE Substudy;
• Reduction in liver fibrosis as assessed by change from Baseline in impedence
ultrasonography in the Impedence Ultrasonography Substudy.
• Subgroup analysis to be conducted: The impact of IgG4 status on outcome. IgG4
positive subjects will be compared to IgG4 negative subjects across all
endpoints.
Safety: All adverse events and laboratory findings will be summarized by
treatment arm will be collected throughout the study.
Background summary
PSC is a chronic disease of the bile ducts of unknown etiology, which is
characterized by a fibrosing cholangitis leading to inflammation, cholestasis
and cirrhosis. No specific treatment exists for PSC. These patients has also
an increased risk of developing a ductal tumor. The mortality from PSC is
estimated to be 35% over 10 years.
Current treatment is treatment of the symptoms such as use of antibiotics. The
only therapeutic option available to PSC patients is liver transplantation.
Lysyl oxidase like-2 (LOXL2) is an extracellular matrix enzyme that is a member
of the lysyl oxidase protein. These enzymes play a role in cross-linking
proteins such as collagen and elastine. As a result, they can promote the
remodelling of the extracellulair matrix. Published literature and studies by
Gilead indicate that LOXL2 plays a central role in development in pathological
stroma in fibrotic diseases by activating and recruiting fibroblasts to the
pathologic site.
Simtuzumab is a humanized monoclonal antibody (IgG4 isotype) to human LOXL2,
which inhibits LOXL2 enzymatic activity.
It is postulated that the use ofsimtuzumab in the setting of PSC could halt the
progression of fibrosis or even reversefibrosis and result in regression of
bile duct strictures and in cirrhosis, preventing complications of PSC and
progression to end-stage liver disease.
Study objective
The primary objective of this study is:
• To evaluate whether simtuzumab (formally referred to as GS-6624) is effective
at preventing the progression of liver fibrosis in subjects with PSC.
The secondary objectives of this study include the following:
• To assess the safety of simtuzumab in subjects with PSC;
• To assess the pharmacokinetics of simtuzumab in subjects with PSC;
• To assess the immunogenicity of simtuzumab in this population;
• To assess whether baseline serum LOXL2 levels are predictive of response to
simtuzumab therapy (active groups) and/or prognostic for disease progression
(placebo group);
• To compare different efficacy assessment tools in this population;
• To determine whether non-invasive measures of fibrosis can predict regression
of fibrosis and reversal of cirrhosis in this population.
Study design
This is a Phase 2b dose-ranging, randomized, double-blind, placebo-controlled
clinical trial designed to assess the efficacy and safety of simtuzumab in
subjects with PSC.
Subjects with PSC will be randomly assigned in a 1:1:1 ratio to treatment with
weekly subcutaneous injections of simtuzumab in one of the following three
Treatment Arms:
• Treatment Arm A - 75 mg of simtuzumab; n= 75
• Treatment Arm B - 125 mg of simtuzumab; n= 75
• Treatment Arm C - Placebo; n= 75
Randomization will be stratified based on the presence or absence of elevated
serum IgG4 levels (>140 mg/dL). The treatment phase of the study will last 96
weeks, with an interim analysis planned after the last randomized subject
completes the Week 48 Visit or is withdrawn from the study.
Intervention
Simtuzumab is a humanized IgG4 monoclonal antibody against LOXL2. It is
administered by subcutaneous injection once per week. In this study, there will
be 3 different blinded treatment arms:
• Treatment Arm A: 75mg of simtuzumab; n = 75
• Treatment Arm B: 125mg of simtuzumab; n = 75
• Treatment Arm C: Placebo; n = 75
Subjects will be provided with single use vials of simtuzumab or matching
placebo and will be taught how to draw up the medication and self administer
it. Treatment Arm A subjects will be provided with simtuzumab at a
concentration of 75 mg/ml, Treatment Arm B subjects with simtuzumab at a
concentration of 125 mg/ml and Treatment Arm C subjects with placebo. All
subjects will inject 1cc of study medication subcutaneously once per week for a
total of 96 weeks.
Study burden and risks
Simtuzumab has been given to a small number of patients with advanced cancers
and lung fibrosis. The most common adverse events seen to date have been
fatigue, high blood pressure, diarrhea, headache, mouth ulcers, nausea,
achiness, decreased appetite, chills, redness at the site of the injection,
joint pain and joint stiffness. Abdominal pain has also been reported.
Simtuzumab appears to be well tolerated, but because this study medication is
only given to a limited number of patients it is possible that not previously
seen side effects will appear.
Risks and adverse events related to simtuzumab include those which are:
- Reaction at the site of drug self-injection (likely)
- The most common side effects reported in studies to date are fatigue and
diarrhea (likely)
- Impaired wound healing (less likely)
- Bleeding (rare but serious)
Other risks:
- The development of anti-drug antibodies:
- Inflammatory bowel disease (IBD): UC co-exists with PSC in about 70% of
patients. The effect of simtuzumab on the disease course of UC is unknown, but
since simtuzumab affects collagen cross-linking, an important step in wound
healing in chronic diseases, the potential exists that it could make it worse.
As with taking any drug, there is a risk of an allergic reaction.
Liver biopsy risks
• Pain and discomfort
• Bleeding at the biopsy site
• Possible internal bleeding
• Infections at the biopsy site or internal organs
• Puncture of internal organs
• Allergic reaction to the anesthetic
• 1 in 10,000 risk of death risk of death from a complication resulting from a
liver biopsy
MRCP and MRE risks:
Implanted medical devices that contain metal may malfunction or cause problems
during an exam.
Blood drawing risks
- pain
- bruising
- feeling lightheaded
- fainting
- infection at the site of the blood draw.
This study consist of a screening, treatment phase (96 weeks) and a follow-up
visit. A patient will undergo the following procedures: blood draws, urine
draws, vital signs, physical exam, liver biopsy, and MRCP.
Patient will be trained to self-inject simtuzumab once a week.
Please refer for a complete overview to the Schedule of Events in the protocol.
Lakeside Drive 333
Foster City 94404, CA
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Lakeside Drive 333
Foster City 94404, CA
US
Listed location countries
Age
Inclusion criteria
1. Males and females 18 - 70 years of age;
2. Willing and able to provide informed, written consent;
3. Chronic cholestatic liver disease of at least 6 months* duration;
4. Liver biopsy consistent with PSC; If a liver biopsy has been performed
within 3 months of the Screening Visit, tissue from that biopsy may be
used as the screening biopsy. Slides would be re-cut from the existing
tissue block and submitted for central reader assessment. Some subjects
with PSC may have a normal liver biopsy, in the event of a normal liver
biopsy, the subject must have an abnormal MRCP;
5. MRCP consistent with PSC; Some subjects with PSC may have a
normal MRCP, in the event of a normal MRCP, the subject must have an
abnormal liver biopsy;
6. Exclusion of other causes of liver disease including viral hepatitis, alcoholic liver disease, primary biliary cirrhosis and secondary sclerosing cholangitis;
7. Must be willing and able to comply with all study requirements;
8. Must have AST and ALT <= 10 x clULN;
9. Must have serum creatinine < 2.0 mg/dL (176.8µmol/L);
10. Female subjects of childbearing potential must have a negative serum pregnancy test prior to starting study treatment. For the purposes of this study, a female subject of childbearing potential is a woman who has not had a hysterectomy, bilateral oophorectomy, or medically-documented ovarian failure. Women <= 50 years of age with amenorrhea of any duration will be considered to be of childbearing potential;
11. All sexually active female subjects who are of childbearing potential must agree to use a highly effective method of contraception during heterosexual intercourse from the Screening Visit throughout the study period and for 90 days following the last dose of study drug. If females utilize hormonal agents as one of their contraceptive methods, the same hormonal method must have been used for at least 1 month before study dosing. Females on hormonal methods must utilize a barrier method as the other form of contraception;
12. Lactating females must agree to discontinue nursing before study
investigational medicinal product administration;
13. Male subjects, if not vasectomized, are required to use barrier
contraception (condom plus spermicide) during intercourse from
screening through to study completion and
for 90 days from the last dose of study investigational medicinal product.
Exclusion criteria
1. Pregnant or breast feeding;
2. Any evidence of hepatic decompensation past or present, including ascites, episodes of hepatic encephalopathy, variceal bleeding or a prolonged PT/INR;
3. HCV RNA positive;
4. HBsAg positive;
5. Positive anti-mitochondrial antibody;
6. Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1oz/25mL of alcohol is present in 1 12oz/300mL beer, 1 4oz/125mL glass of wine, and a 1 oz/25mL measure of 40% proof alcohol)
7. Moderately active UC defined as either a partial Mayo score of > 4,
bleeding score of >1, or current use of oral corticosteroid therapy
and/or any inhibitor of TNF-α or α4β7 integrin antagonist;
8. Positive urine screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening may be included in the study. Subjects with a positive urine drug screen due to prescription opioid-based medications are eligible if the prescription and diagnosis are reviewed and approved by the investigator.
9. Clinically significant cardiac disease;
10. History of cholangiocarcinoma. If a dominant stricture is found, cholangiocarcinoma must be ruled out by brush cytology or biopsy prior to randomization;
11. History of cancer, other than non-melanomatous skin cancer, within 5 years prior to screening;
12. Ascending cholangitis within 60 days of screening;
13. Presence of a percutaneous drain or bile duct stent;
14. Major surgical procedure within 30 days prior to screening or the presence of an open wound;
15. Known hypersensitivity to the investigational product or any of its formulation excipients;
16. History of bleeding diathesis within 6 months of screening;
17. Unavailable for follow-up assessment or concern for subject*s compliance with the protocol procedures;
18. Participation in a clinical trial of an investigational drug or device within 30 days prior to screening;
19. Any other condition that in the opinion of the investigator renders the subject a poor risk for inclusion into the study. Examples of such conditions may include, but are not limited to, systemic lupus erythematosus, chronic obstructive lung disease and chronic pancreatitis.
20. For France only: Subjects benefitting from a legal protection measure
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 | EUCTR2012-002473-61-NL |
| CCMO | NL46201.078.13 |