The primary objective of the study is:To assess the efficacy of TUDCA in slowing disease progression in patients with ALS during the treatment period compared to the lead-in phase), as measured by ALSFRS-R.
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the study is:
* To assess the efficacy of TUDCA in slowing disease progression in patients
with ALS during the treatment period compared to the lead-in phase), as
measured by ALSFRS-R.
Secondary outcome
The secondary objectives of this study are:
* To assess the efficacy of TUDCA in slowing disease progression and functional
impairment in patients with ALS, as measured by the survival time, the ALSAQ-40
questionnaire, FVC, the EQ-5D, and muscle force
* To assess the long term safety and tolerability of TUDCA for up to 18 months
in patients with ALS
Background summary
Amyotrophic lateral sclerosis (ALS) is a chronic non-communicable
neu-rodegenerative rare disease, affecting some 40,000 individuals in Eu-rope,
and causing around 11,000 death. Although much has been achieved over the last
two decades in understanding the disease com-plexity in ALS, there is a
pressing need to find disease-modifying thera-pies that will slow disease
progression and enable patients to gain any length in survival. Although this
is a formidable challenge, there is one drug (riluzole) that slightly prolongs
survival in ALS and is still the only agent with a *disease modifying* effect.
The effect of riluzole on surviv-al in ALS is modest, but indicates that
modifying disease progression is a realistic goal in ALS. Nonetheless, all
subsequent ALS drugs tested have failed to deliver advances in patient care.
We propose a novel therapeutic approach to overcome the current therapeutic
impasse. The *Tauroursodeoxycholic in ALS* (TUDCA-ALS) study will take
advantage of the results of a recent proof-of-concept / proof-of-mechanism
phase IIb study showing that, in patients who re-ceived TUDCA in addition to
riluzole, the per-year decline rate of ALS disease functional rating scale
revised (ALSFRS-R) was of about 7 points smaller (on a 0-48 score) compared to
riluzole only. This corresponds to a prolongation of median survival by 4-5
months. In keeping with this observation, an independent phase IIa study showed
that ursodeoxy-cholic acid (UDCA) penetrates into the cerebrospinal fluid (CSF)
of pa-tients with ALS. This strong indication of efficacy is further supported
by the evidence that TUDCA has cytoprotective properties in animal mod-els of
neurodegenerative diseases. Therefore, a large-scale, phase III, clinical trial
is needed to confirm and further measure the efficacy of TUDCA as a disease
modifier in ALS. We have also selected solid biomarkers related to disease
progression and cytoprotective activity to test during the 18-month treatment
period. We have therefore assem-bled a consortium composed of leading European
centres with estab-lished experience in ALS and a strong catching capability on
this patient population.
Study objective
The primary objective of the study is:
To assess the efficacy of TUDCA in slowing disease progression in patients with
ALS during the treatment period compared to the lead-in phase), as measured by
ALSFRS-R.
Study design
This is a Phase III, multicenter, randomised, double-blind, placebo-controlled,
parallel-group study.
Intervention
Tauroursodeoxycholic
Study burden and risks
Previous studies have shown that TUDCA is safe and well tolerated. However, all
medicines can (not) advertise. The most complex side effects of TUDCA are:
occasional nausea, vomiting, soft stools or mild diarrhea, gallstone calcareous
deposits and itching. Keep in mind that you can not experience any of these
side effects.
To date, no interactions with other drugs have been reported. At this moment we
do not know any contraindications for the use of TUDCA.
Treatment with TUDCA should be avoided:
* Substances that limit the absorption of bile acids [such as colestyramine
(Questran) from colestipol (Colestid)];
* Gastric acid inhibitors containing aluminum hydroxide and / or smectites
(aluminum oxide) (such as Maalox);
* estrogens (such as oestradiol estriol);
* Medications that lower plasma cholesterol from the removal of cholesterol by
the gallbladder (estrogens, hormonal contraceptives, single statins and
fibrates), and
• Hepatogenic drugs, that are drugs that affect the leg.
The use of TUDCA
Via Alessandro Manzoni 56
Rozzano Milano 20089
IT
Via Alessandro Manzoni 56
Rozzano Milano 20089
IT
Listed location countries
Age
Inclusion criteria
1. laboratory-supported, probable, or definite ALS diagnosis, as defined by El
Escorial Revised ALS diagnostic criteria
2. Disease duration <= 18 months
3. No swallowing difficulty (4 at ALSFRS-R swallowing subscore)
4. Able to perform reproducible pulmonary function tests
5. Forced vital capacity >=70% of normal
6. Stable on riluzole treatment for 3 months in the lead-in period
7. Signed informed consent
All patients who entered and completed the TUDCA-ALS clinical trial can be
included in the open-label TUDCA-ALS Extension.
Inclusion criteria:
1. Completion of the visit M18 (Month 18) of the TUDCA-ALS clinical trial.
2. Signed informed consent for participation in the TUDCA-ALS Extension
sub-study.
Exclusion criteria
1. Treatment with edaravone or other unaccepted concomitant therapy (substances
inhibiting the intestinal absorption of bili-ary acids, antacids containing
aluminium hydroxide and/or smectites, estrogens and drugs acting by lowering
plasmatic cholesterol; drugs increasing biliary clearance of cholesterol,
hepatolesive drugs)
2. Other causes of neuromuscular weakness
3. Presence of other neurodegenerative diseases
4. Significant cognitive impairment, clinical dementia or psychiat-ric illness
5. Severe cardiac or pulmonary disease
6. Other diseases precluding functional assessments
7. Other life-threatening diseases
8. At the time of screening, any use of non-invasive ventilation for any
portion of the day, or mechanical ventilation via tracheost-omy, or on any form
of oxygen supplementation
9. Gastrointestinal disorder that is likely to impair absorption of study drug
from the gastrointestinal tract
10. Has taken any investigational study drug within 30 days or five half-lives
of the prior agent, whichever is longer, prior to dosing
11. Any clinically significant laboratory abnormality
12. Other concurrent investigational medications
13. Active peptic ulcer
14. Previous surgery or infections of small intestine
15. Patients unable to easily swallow the treatment pills at time of enrolment
16. Occurrence of frequent biliary colic, biliary infections, severe pancreatic
abnormalities
17. Subjects who weigh 88 lbs (40 kg) or less at screening
18. Sieric Aspartate aminotransferase or alanine aminotransferase
concentrations more than 3 times the upper limit of normal
19. Creatinine clearance 50 ml/min or less
20. Any clinically significant neurological, haematological, autoim-mune,
endocrine, cardiovascular, neo-plastic, renal, gastroin-testinal, or other
disorder that, in the Investigator's opinion, could interfere with the
subject's participation in the study, place the subject at increased risk, or
confound interpretation of study results
21. Consideration by the investigator, for any reason, that the sub-ject is an
unsuitable candidate to receive TUDCA or that the subject is unable or unlikely
to comply with the dosing schedule or study evaluations
22. The patient is sexually active and is not willing to use highly ef-fective
contraception during the study and up to 90 days after the day of last dose
Exclusion criteria:
1. Treatment with edaravone or other unaccepted concomitant therapy (as per
section 8 of the main TUDCA-ALS clinical trial protocol)
2. Consideration by the investigator, for any reason, that the subject is an
unsuitable candidate to re-ceive TUDCA or that the subject is unable or
unlikely to comply with the dosing schedule or study evaluations
3. The patient of reproductive potential is sexually active and is not willing
to use highly effective con-traception during the study and up to 90 days after
the day of last dose (see Contraceptive Guidance in Appendix A)
4. The patient is pregnant or breast feeding
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 | EUCTR201800272222-NL |
| ClinicalTrials.gov | NCT03800524 |
| CCMO | NL69414.041.19 |