Primary* To evaluate the effect of RO7049665 on time to relapse following forced CCS tapering as measured by the hazard ratio between 7.5 mg RO7049665 and placebo.Secondary* To assess changes in alanine aminotransferase (ALT), aspartate…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints
- Time to relapse from randomization.
Secondary outcome
Secondary Endpoints
- ALT, AST, and IgG (for both absolute and relative [ULN]) over time.
- Time to relapse from randomization.
- Incidence and severity of adverse events.
- Changes in vital signs, physical examination, ECG parameters, and safety
laboratory parameters.
- ADA emergence and neutralizing potential.
Background summary
AIH may present as acute or chronic hepatitis or as well established cirrhosis;
in rare cases, it presents as fulminant hepatic failure. Patients experience
unspecific symptoms like fatigue, upper abdominal discomfort, mild pruritus,
anorexia, myalgia, arthralgia, rashes (including acne), and amenorrhea.
Untreated AIH can lead to liver cirrhosis, development of hepatocellular
carcinoma, and finally to death.
AIH is a rare disease with a prevalence of 16 to 18 affected people per 100 000
inhabitants in Europe (EASL 2015). It can affect people of all ages and sexes,
though the female to male ratio is approximately four to one. AIH is
characterized by a large heterogeneity of clinical, laboratory, and
histological manifestations and therefore difficult to diagnose. If
hypergammaglobulinemia is present, AIH should always be taken into
consideration (EASL 2015). A simplified AIH score has been developed to
facilitate the diagnosis in patients with histological evidence of hepatitis.
There is currently no approved treatment for AIH. Patients with AIH usually
respond rapidly to immunosuppressive treatment (CCS +/- non-specific
immunosuppressants [NSIs]) but relapse quickly after its tapering. Most
patients need to be on immunosuppressive treatment for extended periods and
often for life. Side effects of long-term immunosuppressive treatment can be
quite severe and include osteoporosis, muscle wasting, skin manifestations, and
endocrine effects like steroid-induced diabetes.
Therefore, there is an unmet medical need in patients with AIH to replace the
current standard of care (SoC) with a less burdening maintenance.
Study objective
Primary
* To evaluate the effect of RO7049665 on time to relapse following forced CCS
tapering as measured by the hazard ratio between 7.5 mg RO7049665 and placebo.
Secondary
* To assess changes in alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and IgG over time and by dose.
* To evaluate the effect of RO7049665 on time to relapse following forced CCS
tapering as measured by the hazard ratio between 3.5 mg RO7049665 and placebo.
* To evaluate the safety and tolerability of RO7049665 in participants with
AIH.
Study design
This is an event-driven study, which means that participants stay in the study
and on treatment until the participant experiences an event (e.g., ALT rises >
2 x upper limit of normal [ULN] or IgG increases > 1.5 x ULN), the necessary
number of events (a total of 45 events) is reached, the participant stops for
other reasons or withdraws consent, or the study ends.
Patients eligible for the study must be in biochemical remission for at least 2
years, be on stable treatment (CCSs * non-specific immunosuppressants [NSIs])
for at least 6 months prior to study entry, and show no signs of inflammation
(HAI * 3) on a liver biopsy taken no more than 12 months prior to
randomization. For eligible patients this will be the first attempt to taper
out CCS completely.
At study entry, the disease status of the participants should allow for a
stepwise removal of all immunosuppressive treatment. Participants will start
with study treatment on study Day 1 and start tapering CCS use from Day 8
onwards (see tapering schedule, Section 1.3, Table 3) to allow for complete CCS
withdrawal within a maximum of 12 weeks, depending on the starting dose. Last
dose of NSI therapy, if any, will be taken on study Day -1.
Randomization in a 1:1:1 fashion will occur after patient eligibility is
confirmed and before the first dose of study drug is administered.
Randomization will be stratified by equivalent prednisolone dose (* 7.5 mg
daily versus > 7.5 mg daily or dual therapy [CCS any dose, plus RO7049665
NSI]). Two interim analyses are planned. The first is planned for futility once
25% of events (i.e.,12 events) are observed. The second interim analysis for
efficacy and futility is planned once 50% of events (i.e., 23 events) are
observed.
Intervention
See section E4 of the ABR form
Study burden and risks
RO7049665 has been tested in a study (WP39826) with 38 healthy volunteers.
RO7049665 was given as a single injection, at doses ranging from 1.5 microgram
(*g; one millionth of a gram) to 7500 µg (or 7.5 mg). The most frequently
reported side effects of the study were injection site reactions (see Local
Pain and Skin Reactivity), common colds and headache. Most of the side effects
reported in this study were of mild intensity with no severe or serious events.
In another ongoing study (WP40161), doses of 3.5 mg and 7.5 mg of RO7049665 are
tested in patients with ulcerative colitis. Patients receive 1 dose of
RO7049965 (or placebo) every two weeks for a total of 4 doses. To date 30
patients have received RO7049965. The most frequently reported side effects to
date are injection site reactions and eosinophilia (increase of a specific type
of white blood cell [eosinophils] known to combat certain types of infections
and parasites. These cells also control mechanisms around allergy and asthma).
Most of the side effects reported in this study are of mild intensity with a
low number of moderate to severe events.
In this study, the same two doses of RO7049665 will be tested (3.5 mg and 7.5
mg).
Side Effects due to Corticosteroid Tapering
The corticosteroid tapering is designed to minimize any possible withdrawal
effects; however, it cannot be ruled out that the patient may experience any
withdrawal effect, including weakness, fatigue, abdominal pain, nausea,
vomiting and possibly disease flare.
Side Effects due to Immune Suppression
RO7049665 works by increasing regulatory T-cells, which may decrease the body*s
natural defenses against infection and tumors (immunosuppression).
Immunosuppression is not expected at the doses studied because the body
naturally uses regulatory T-cells in controlling excessive immune activity,
including during an infection. It is likely that the risk of immune suppression
is greater in combination with other treatments targeting the immune system.
Therefore the patient will not be allowed to use other immune suppressive
treatments once he/she has stopped taking previous immunosuppressive treatment.
Allergic Reactions
Allergic reactions can occur with any drug and this can be in the form of
itching, difficulty breathing, and a skin rash and/or drop in blood pressure.
In very rare cases, the patient could suffer a life-threatening allergic
reaction. If the patient does experience any such reaction, he/she should tell
the study doctor immediately so that the patient can receive the appropriate
treatment.
Antibodies to the drug
Antibodies which attach to the drug could occur, and could be without signs or
symptoms, or could cause allergic reactions (see above), or a decrease in
effectiveness or concentration of the drug. Very rarely, antibodies to drugs
can also act like antibodies to similar proteins that the body makes normally.
If antibodies to RO7049665 interact with the natural IL 2, a decrease or
absence of IL-2 may occur, which has been associated with autoimmune conditions
such as autoimmune thyroiditis (inflammation of thyroid gland) or Type 1
Diabetes. Antibodies to RO7049665 have been seen in the two previous studies
(WP39826 and WP40161), however, these had no impact on safety and were not
directed against natural IL-2. The patient will be monitored closely for the
possibility of antibodies against the drug in this study and for potential
outcomes such as allergic reactions.
In studies in animals with RO7049665, it was observed that RO7049665 caused a
temporary increase in heart rate, so the heart activity will be monitored
during this study. No increase in heart rate was observed in the two previous
studies.
Risks Associated with Drug Administration
Local Pain and Skin Reactivity
Administration of study drug will be done by injecting under the skin in the
lower belly (abdomen). Local pain and injection site reactions can occur and
include burning, bleeding, itching, bruising, redness, and hive formation.
Injection site reactions of mild intensity were the most frequently reported
side-effect in the two previous studies. If the patient develops a reaction
around the injection site, the study doctors may ask to take a photograph of
the reaction.
Risks Associated with Study Procedures
Blood Sampling
During this study, small amounts of blood will be drawn from a vein and used
for tests that allow the study doctors to see how the patient is doing. Drawing
blood may cause pain where the needle is inserted, and there is a small risk of
bruising or infection at the place where the needle is inserted. Very rarely, a
blockage of the vein or a small nerve injury can occur, resulting in numbness
and pain. However, this will resolve with time. Some people experience
dizziness, upset stomach, or fainting when their blood is drawn.
On days when several blood samples will be taken, we may use a cannula (small
plastic tube) inserted in the arm using a small needle. This cannula may remain
in place for the day and will be taken out before the patient goes home. There
is a small chance of infection by placing the cannula in the arm, but every
medical precaution will be taken to avoid an infection.
Electrocardiogram (ECG)
The patient will have small, soft pads, placed temporarily on different parts
of his/her body. There is no pain or discomfort during an ECG; however, the
area of skin in which the ECG pads will be stuck may need to be shaved, and the
pads may cause a skin reaction such as redness or itching. Taking the pads off
may cause localized irritation to the skin and/or hair loss, similar to having
a plaster taken off.
Biopsies
The patient may feel some amount of pain or discomfort during the biopsy,
including slight stinging pain when a local anesthetic is injected by needle to
numb the area, pressure and dull pain where the biopsy needle is inserted,
discomfort from lying still for an extended time, and soreness at the biopsy
site. If a general anesthetic is used, the patient will not feel pain during
the procedure because he/she will be asleep. There is a risk of injury to
adjacent organs and infection. If the patient chooses to allow collection of
his/her fresh liver tissue, the doctor will explain the risks of the biopsy
procedure to the patient for his/her to decide if you want to participate.
Reproductive Risks
Reproductive Risks for Women
If the patient is pregnant or become pregnant, or if she is currently
breastfeeding, she cannot take part in this study because she or her child may
be exposed to an unknown risk.
If the patient is a woman who can become pregnant, she must have a test that
shows she is not pregnant before she can be enrolled in this study. The patient
may also have further pregnancy tests during the course of the study. If her
urine pregnancy test is positive, a repeat (blood) pregnancy test will be taken
to confirm the result. If the blood test is positive, the patient will not
receive any more study medication.
If the patient can become pregnant, she must agree to remain abstinent or use
birth control methods that are judged to be effective by the study doctor
during this study and within 28 days after the final dose of RO7049665. The
patients should check with the study doctor about the methods of birth control
to use.
The patient should tell the study doctor right away if she suspect that she
have become pregnant during the study (including the 28-day follow up period).
The study doctor will ask for patient's permission to follow up with her on the
outcome of the pregnancy and collect information on the baby.
Possible Risks Associated With Loss Of Privacy
Although the genetic information will not contain any personal identifying
information, there is a very small risk that it could be linked to an outside
public database and used to help identify the patient and his/her blood
relatives. Because some genetic differences can help to predict future health
problems experienced by the patient or his/her blood relatives, this
information might be of interest to health care providers, life insurance
companies, and others. It is possible that genetic information could be used in
ways that would cause the patient or his/her family distress, such as by
revealing that the patient or a blood relative carries a genetic disease.
Avenue Marcel Thiry 77
Bruxelles 1200
NL
Avenue Marcel Thiry 77
Bruxelles 1200
NL
Listed location countries
Age
Inclusion criteria
Inclusion Criteria
Participants are eligible to be included in the study only if all of the
following criteria apply:
Informed Consent
1. Able and willing to provide written informed consent and to comply with the
study protocol according to International Conference on Harmonisation (ICH) and
local regulations.
Age
2. Between 18 to 75 years of age, inclusive, at the time of signing the
informed consent.
Type of Participants and Disease Characteristics
3. Patients with a definite diagnosis of AIH (type 1, 2 and 3) as per
simplified or revised original diagnostic criteria (including response to CCSs)
(Hennes et al 2008).
4. Patients who have been in biochemical remission (complete normalization of
serum transaminases and IgG levels) for * 2 years prior to randomization.
5. Patients who have been on stable treatment (CCSs * NSIs) for at least 6
months prior to randomization.
6. No signs of liver inflammation (HAI * 3) on a liver biopsy taken no more
than 12 months prior to randomization.
7. Patients with AIH who have previously not attempted to taper CCS to 0 mg/day.
Weight
8. Body mass index within the range of 18-35 kg/m2 (inclusive).
Sex and Contraception/Barrier Requirements
9. Male and female participants are eligible.
The contraception and abstinence requirements are intended to prevent exposure
of an embryo to the study treatment. Therefore, the reliability of sexual
abstinence for female enrollment eligibility needs to be evaluated in relation
to the duration of the clinical study and the preferred and usual lifestyle of
the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
or post-ovulation methods) and withdrawal are not acceptable methods of
preventing drug exposure.
A female participant is only eligible to participate if she is not pregnant,
not breastfeeding, and at least one of the following conditions applies:
Women of non-childbearing potential (WONCBP),
OR
Women of childbearing potential (WOCBP), who:
Agree to remain abstinent (refrain from heterosexual intercourse) or use at
least one acceptable contraceptive methods during the treatment period and for
at least 28 days after the final dose of study drug.
The following are acceptable contraceptive methods: bilateral tubal occlusion/
ligation, male sexual partner who is sterilized, established proper use of
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine
devices and copper intrauterine devices, male or female condom with or without
spermicide; and cap, diaphragm, or sponge with spermicide.
Exclusion criteria
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Patients with cirrhosis (F4 fibrosis by Fibroscan®) with significant
impairment of liver function (Child Pugh category B or C).
2. Any other autoimmune disease (including overlap syndrome) requiring
immunomodulating treatment.
3. History of infection with hepatitis B (hepatitis B surface antigen [HBsAg]
positive and/or anti-HBc positive; HBV vaccinated patients are eligible), human
immunodeficiency virus (HIV; positive HIV antibody test), active hepatitis C
virus (HCV) infection (detectable HCV RNA), detection of replicating CMV or
Epstein-Barr virus.
4. Active infections requiring systemic therapy with antibiotic, antiviral or
antifungal treatment or febrile illness within 7 days before Day *1.
5. History of primary or acquired immunodeficiency.
6. Female patients: Pregnant or lactating.
7. Symptomatic herpes zoster within 3 months prior to screening.
8. History of active or latent tuberculosis or a positive Quantiferon* Gold
test.
9. History of clinically significant severe drug allergies, multiple drug
allergies, allergy to any constituent of the product, or intolerance to topical
steroids.
10. Lymphoma, leukemia, or any malignancy within the past 5 years, except for
basal cell or squamous epithelial carcinomas of the skin that have been
resected with no evidence of metastatic disease for 3 years and in situ
carcinoma of the cervix that was completely removed surgically. Breast cancer
within the past 10 years.
11. Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to
severe heart failure New York Heart Association [NYHA] Class III/IV),
pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders (excluding
UC).
12. Any condition or disease detected during the medical interview/physical
examination that would render the patient unsuitable for the study, place the
patient at undue risk or interfere with the ability of the patient to complete
the study in the opinion of the Investigator.
Prior/Concomitant Therapy
13. CCSs of * 5 mg/day (prednisolone-equivalent dose), or < 2.5 mg CCSs
(prednisolone-equivalent dose) plus immune suppressant, or < 3 mg/day
budesonide with or without immune suppressant.
14. CCSs * 20 mg/day (prednisolone-equivalent dose) or > 9 mg/day budesonide.
15. NSI daily dose higher than recommended standard of care therapy.
16. T or B cell-depleting therapy (e.g., rituximab) within the last 12 months
or T- or B-cell number below normal due to depleting therapy.
Prior/Concurrent Clinical Study Experience
17. Leukocyte apheresis within 12 weeks of screening.
18. Donation of blood or blood products in excess of 500 mL within 3 months
prior to screening.
19. Exposure to any investigational treatment within 6 months prior to Day 1.
Laboratory Abnormalities
20. Abnormal hematologic values:
* Anemia (hemoglobin * 9 g/dL)
* Leukocytosis (white blood cells * 2 * ULN)
* Thrombocytopenia (platelet count * 100,000/*L)
* Thrombocytosis (platelet count * 2 * ULN)
* Eosinophilia (eosinophil count * 2 * ULN)
21. Abnormal hepatic enzyme or hepatic function values:
* ALT, AST, or alkaline phosphatase, above normal range
* Total bilirubin * 2 * ULN
* International normalized ratio (INR) * 1.7
* Albumin * 3 g/dL
22. Abnormal biochemistry values:
* IgG above normal range
Other Exclusions
23. History of regular alcohol consumption within 2 months of screening defined
as:
An average weekly intake of * 14 drinks for men or * 7 drinks for women. One
drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces
(150 mL) of wine, or 1.5 ounces (45 mL) of 80 proof distilled spirits
(equivalent to 40 vol%).
24. Any suspicion or history of illicit drug use.
25. Patients under judicial supervision, guardianship, or curatorship.
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 | EUCTR2020-003990-23-NL |
| CCMO | NL75913.056.21 |