Primary:To evaluate the efficacy of 3 doses of RhuDex vs placebo for the treatment of PBC in patients with an inadequate response to UDCA.Secondary:• To identify efficacious RhuDex dose(s) for the treatment of PBC for further evaluation in phase III…
ID
Source
Brief title
Condition
- Gallbladder disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Relative change (%) in ALP from baseline to EOT.
Secondary outcome
• Proportion of patients with at least 10%, 20%, and 40% reduction in ALP
between baseline and EOT,
• Proportion of patients with normalisation of ALP (< ULN) at least at one
post-baseline visit up to EOT,
• Proportion of patients with partial normalisation of ALP (< 1.5x ULN) at
least at one post-baseline visit up to EOT,
• ALP at each trial visit (screening to follow-up),
• Absolute and relative changes (%) of ALP from baseline to each visit up to
EOT, and from EOT to the follow-up visit,
• Gamma-glutamyltransferase (γ-GT), AST, ALT, and total and conjugated
bilirubin levels at each trial visit (screening to follow-up),
• Absolute and relative changes (%) of γ-GT, AST, ALT and total and conjugated
bilirubin levels from baseline to each visit up to EOT, and from EOT to the
follow-up visit.
Background summary
This double-blind, randomised, multi-centre, placebo-controlled, comparative
phase II trial will compare oral treatment with 50, 100 or 200 mg/day RhuDex
granules vs placebo granules for the treatment of PBC.
Previous phase I trials evaluated the safety and PK of different formulations
of RhuDex in healthy volunteers. To date only one study was performed in
patients (indication RA). The planned trial is expected to provide efficacy and
safety data for RhuDex granules in patients with PBC.
The tested dosing regimen was found to be safe and established a systemic
exposure (plasma concentration) in the range of the in vitro doses with
relevant pharmacodynamic effects. The PK profile of RhuDex is characterised by
accumulation in the hepatobiliary system providing a natural targeting for PBC.
Efficacy data will include biochemical and symptomatic endpoints. Furthermore,
the planned trial should provide additional information on a safe and effective
dose from 25 to 100 mg RhuDex BID administered to humans. A treatment duration
of 12 weeks is considered sufficient to detect changes in surrogate markers of
the disease. All efficacious PBC treatments have shown an effect on ALP within
8 weeks, e.g. UDCA, OCA, and bezafibrate. Therefore, a potential treatment
effect by RhuDex is expected to be also seen within 12 weeks.
The patients will be followed up until 4 weeks after the last dose of the
investigational medicinal product (IMP), which is much longer than 5 times the
half-life of RhuDex (about 120 hours).
As all patients will continue standard of care treatment with UDCA, a placebo
arm will be included as control due to regulatory recommendations to evaluate
dose-related benefits and adverse effects in randomised, double-blind, placebo
controlled studies.
Based on the results obtained in this trial, the optimal dose with regard to
clinical outcomes might be evaluated further in a phase III confirmative trial.
Study objective
Primary:
To evaluate the efficacy of 3 doses of RhuDex vs placebo for the treatment of
PBC in patients with an inadequate response to UDCA.
Secondary:
• To identify efficacious RhuDex dose(s) for the treatment of PBC for further
evaluation in phase III,
• To study safety and tolerability of RhuDex.
Study design
This is a double-blind, randomised, multi-centre, placebo-controlled,
comparative, exploratory phase II dose-finding trial. The trial will be
conducted with 4 treatment groups in the form of a parallel group comparison
and will serve to compare oral treatment with either 50, 100 or 200 mg/day
RhuDex gastro-resistant granules vs placebo granules for the treatment of PBC.
The up to 4-week screening and randomization period will be followed by a
12-week double-blind treatment period and a 4-week follow-up period.
The trial will be performed according to a 2-stage group-sequential adaptive
design with one planned interim analysis.
Double-blind, randomised (1:1:1:1) treatment phase:
Patients will be randomised to receive a 12-week, double-blind treatment with:
Group A: RhuDex 25 mg (31.75 mg RhuDex choline salt) twice daily (BID)
1 sachet with a blend of 750 mg RhuDex granules and 2,250 mg placebo granules
Group B: RhuDex 50 mg (63.5 mg RhuDex choline salt) BID
1 sachet with a blend of 1500 mg RhuDex granules and 1,500 mg placebo granules
Group C: RhuDex 100 mg (127 mg RhuDex choline salt) BID
1 sachet with 3,000 mg RhuDex granules
Group D: Placebo granules for RhuDex BID
1 sachet with 3,000 mg placebo granules
Follow-up phase: Until 4 weeks after the patient*s individual end of treatment.
Blinding is achieved by the application of the same amount of granules for each
verum dose and placebo to each patient. Placebo granules match verum granules
in size, taste and appearance; the granules of both verum and placebo are
filled in identical sachets.
All patients will continue their pre-trial dose of UDCA throughout trial
participation without changing the dosing regimen.
Intervention
Double-blind, randomised (1:1:1:1) treatment phase:
Patients will be randomised to receive a 12-week, double-blind treatment with:
Group A: RhuDex 25 mg (31.75 mg RhuDex choline salt) twice daily (BID)
1 sachet with a blend of 750 mg RhuDex granules and 2,250 mg placebo granules
Group B: RhuDex 50 mg (63.5 mg RhuDex choline salt) BID
1 sachet with a blend of 1500 mg RhuDex granules and 1,500 mg placebo granules
Group C: RhuDex 100 mg (127 mg RhuDex choline salt) BID
1 sachet with 3,000 mg RhuDex granules
Group D: Placebo granules for RhuDex BID
1 sachet with 3,000 mg placebo granules
Study burden and risks
Treatment with RhuDex can lead to undesirable effects or discomforts.
These side effects are common (occurs in 1 in 10 people or more):
- Headache,
- Blurred vision,
- Diarrhoea, frequent bowel movements, vomiting, nausea,
- Common cold (nasopharyngitis),
- Decreased appetite,
- Dizziness,
- Cough,
- Hot flush,
These side effects occur, but not often:
- Rapid heartbeat (palpitations),
- Irritation and redness of the membrane covering the eye (conjunctivitis), dry
eye, visual impairment,
- Upper abdominal pain, abdominal pain, constipation, dyspepsia, gas/upset
stomach, lip pain,
- Chest discomfort, influenza like illness, fatigue,
- Inflammation of stomach and intestine (viral gastroenteritis), oral herpes,
upper respiratory tract infection, shingles (herpes zoster),
- Alanine aminotransferase (liver value) increased, abnormal heart activity
(electrocardiogram QT corrected interval prolonged), hepatic enzymes increased,
liver function test abnormal,
- High blood sugar (hyperglycemia),
- Musculoskeletal pain,
- Sleepiness (somnolence),
- Difficulty breathing (dyspnoea), throat/upper neck (pharyngolaryngeal) pain,
- Increased sweating (hyperhidrodis),
- Flushing, inflammation of a vein (phlebitis).
RhuDex may also cause side effects that are unknown.
Tests
The study-related tests may be associated with risks or lead to discomforts:
• Blood sampling: This might cause discomfort, bruising or, unusually, clotting
of the vein at the site where the needle is inserted. In rare cases, it might
cause venous inflammation (thrombophlebitis) or nerve injury.
At each visit, approx. 30 ml blood will be sampled. In total, approx. 150 ml
blood will be sampled in the course of the study. This amount should not cause
any problems in adults. In comparison: at the blood bank, 500 mL of blood is
collected at one time
• Electrocardiogram (ECG): You will be asked to lie flat on a table, and
several small electrode pads (like stickers) will be placed on the body which
may cause some transient redness or itching.
• Ultrasound: This application requires use of a lubricant jelly to enhance
transmission of the sound waves. The procedure is non-invasive and poses no
relevant known risks to you other than a gentle pressure. Please let your
physician know about possible allergies to the contact jelly.
• Fibroscan (only if available at your study site): This technology is similar
to an ultrasound device. It is non-invasive and poses no relevant known risks
to you other than a gentle pressure. Please let your physician know about
possible allergies to the contact jelly.
Subjects have to visit the clinic more frequent (6 times in 16 weeks) then
standard of care (once per year).
Tempelzicht 8
3210 - Linden (Vlaams-Brabant) 3210
NL
Tempelzicht 8
3210 - Linden (Vlaams-Brabant) 3210
NL
Listed location countries
Age
Inclusion criteria
Patients who meet all of the following criteria can be enrolled into the trial:
1. Patient is able to understand the information on the trial and has signed
the informed consent form,
2. Male or female patients >= 18 and < 75 years,
3. PBC verified by at least 2 out of the following 3 criteria (consistent with
EASL practice guidelines [2017]) :
• Chronic cholestatic disease (e.g. elevated serum ALP) of at least 6 months
duration,
• Positive AMA titer or presence of PBC-specific antibodies,
• Liver biopsy compatible with the diagnosis of non-cirrhotic PBC,
4. UDCA treatment for at least 6 months (with a stable dose for >= 3 months of
at least 12 mg/kg/day) prior to baseline,and no foreseen changes of the dosing
regimen throughout trial participation,
5. Inadequate response to UDCA treatment defined by serum ALP levels between
1.5x and 10x the upper limit of normal (ULN) at screening,
6. Women of childbearing potential agree to use during the entire duration of
the trial and until 4 weeks following the last dose of trial treatment a highly
effective method of birth control, defined as those which result in a low
failure rate (i.e. less than 1% per year) when used consistently and correctly
such as implants, injectables, combined oral contraceptive methods, some
intrauterine devices (IUDs), sexual abstinence, or vasectomised partner. Women
of non-childbearing potential (surgically sterile [e.g. hysterectomy, bilateral
salpingectomy, bilateral oophorectomy], or postmenopausal with at least 2 years
without spontaneous menses) may be included. The investigator is responsible
for determining whether the patient uses adequate birth control for trial
participation
Exclusion criteria
Patients who meet one or more of the following criteria are not allowed to be
enrolled into the trial:
1. History or presence of other relevant concomitant liver diseases including:
• Positive hepatitis B or C serology: hepatitis B surface antigen (HBsAg+),
antibodies against hepatitis B core antigen (anti-HBc+), antibodies against
hepatitis C virus (anti-HCV+),
Note: Patients with anti-HBc+ only and negative hepatitis B virus
(HBV)-deoxyribonucleic acid (DNA) as well as patients with anti-HCV+ only and
negative HCV-ribonucleic acid (RNA) may be included
Primary Sclerosing Cholangitis,
• Wilson*s Disease,
• Haemochromatosis,
• Current histologic and serologic evidence to support a clinical diagnosis of
concomitant autoimmune hepatitis requiring treatment,
• Nonalcoholic steatohepatitis (NASH),
• Alcoholic steatohepatitis (ASH),
• Cholangiocarcinoma,
• Drug-induced liver disease,
• Suspected or proven liver cancer.
2. Treatment with any of the following drugs within the last 4 weeks prior
to screening: any glucocorticosteroids, azathioprine or other immunosuppressive
drugs (e.g. cyclophosphamide, cyclosporine, methotrexate, tacrolimus,
6-mercaptopurine, colchicine) orpentoxyfylline,
Note: Treatment with dermal, inhalative, or nasal topical glucocorticosteroids
for up to 10 days within the last 4 weeks prior to screening or as planned
concomitant treatment for up to 10 days/4 weeks is allowed.
3. Treatment with farnesoid X receptor-agonists and biologics (e.g. anti-TNF-α
therapy) within the last 8 weeks prior to screening,
4. Treatment with fibrates unless on stable dose for 8 weeks prior to screening
and no foreseen changes of the dosing regimen throughout trial participation,
5. Liver cirrhosis confirmed by an accepted diagnostic procedure (e.g.
histology, fibrosis-4 [FIB-4] score > 4.03, fibroscan >= 16.9 kPa ),
6. History or presence of hepatic decompensation (e.g. variceal bleeding
hepatic encephalopathy or poorly controlled ascites),
7. Serum albumin less than 3.2 g/dL, at screening,
8. Total bilirubin > 2x ULN, at screening,
9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5x ULN
at screening visit,
10. History of stroke or coronary artery disease,
11. History of sudden death or cardiovascular death before the age of 50 in any
first degree relative,
12. History or family history of hereditary clotting disorder,
13. Any known relevant infectious disease (e.g. active tuberculosis, acquired
immunodeficiency syndrome-defining diseases),
14. Abnormal renal function (glomerular filtration rate estimated from cystatin
C < 60 mL/min) at screening visit,
15. Thyroid-stimulating hormone > ULN at screening (elevated levels [4.2-10 µU/
mL] are acceptable if free thyroxine 4 is measured and within the normal range),
16. Current history of significant alcohol consumption (> 30 g/day in men, > 20
g/day in women on average) for a period of more than 3 consecutive months
within 1 year prior to screening,
17. Inability to reliably quantify alcohol consumption as judged by the
investigator,
18. Any illness or medical conditions that are unstable or could jeopardise the
safety of the patient and his/her compliance in the trial or might interfere
with the trial results,
19. Previous and concurrent HIV infection,
20. Previous or concurrent cancer except cervical carcinoma in situ, treated
basal cell carcinoma, or any cancer curatively treated < 3 years before trial
entry,
21. Known intolerance/hypersensitivity to the Investigational Medicinal Product
(IMP) or its excipients, or to drugs of similar chemical structure or
pharmacological profile,
22. Well-founded doubt about the patient*s cooperation, e.g. because of
addiction to alcohol or drugs,
23. Existing or intended pregnancy or breast-feeding,
24. Participation in another clinical trial and having received IMP within the
last 30 days or <= 5 terminal elimination half-lives of previous IMP, whichever
is longer, prior to screening visit, simultaneous participation in another
clinical trial, or previous participation in this trial and having received IMP,
25. Dependency (as an employee or relative) on the sponsor or investigator,
26. Commitment to an institution by virtue of an order issued either by the
judicial or the administrative authorities,
27. Legal incapacity or limited legal capacity.
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 | EUCTR2020-001961-34-NL |
| CCMO | NL74708.056.20 |
| Other | see J |