The objective is to compare the efficacy and safety of intravenous high-dose penicillin G and hydrocortisone versus placebo in combination with riluzole in the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS).
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline to week 48 in Amyotrophic Lateral Sclerosis Functional
Rating Scale - Revised (ALSFRS-R).
Secondary outcome
Changes in both treatment arms:
- Survival
- Change in sVC (measure for lungcapacity)
- Change in muscle strength
- Change in plasma creatinin
- Mean time spent in each stage of the King*s staging system and ALS
Milano-Torino Staging system (ALS-MITOS).
- Time to gastrostomy defined as the time from randomization to the time of
the gastrostomy.
- Changes in score on the EQ-5D-5L.
- Change in the Center for Neurological Study - Bulbar Functional Scale
(CNS-BFS)
- Safety: Number of Serious Adverse Events (SAEs), changes on clinical
examination including vital signs and weight, laboratory exams (biochemistry
and hematology).
Background summary
In a recent case series improvement and/or stabilization of neurological
deficits was reported in ALS patients in response to treatment with penicillin
G and hydrocortisone. Although limited preclinical data on available penicillin
G and hydrocortisone is available, there is a considerable body of evidence
suggesting that beta-lactam antibiotics, the category to which penicillin
belongs, might have neuroprotective effects in ALS by inducing EAAT2 expression
leading to lower levels of glutamate and hereby ameliorating excitotoxicity.
Study objective
The objective is to compare the efficacy and safety of intravenous high-dose
penicillin G and hydrocortisone versus placebo in combination with riluzole in
the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS).
Study design
A mono-center randomized, placebo-controlled, double blind Phase 2 trial of
Penicillin G and Hydrocortisone in ALS
Intervention
A total of 16 patients will be randomized in 2 groups, where one group will
receive intravenous penicillin G (1 - 20 million units in escalating dose)
during 3 weeks and 100 mg hydrocortisone during the first 2 weeks in
combination with riluzole at 3-month intervals over the course of 48 weeks and
the other group will receive placebo (intravenous 0.9% saline solution
identical to the actual medication) for 3 weeks in combination with riluzole at
3-month intervals over the course of 48 weeks.
Study burden and risks
Patients will undergo 4 courses of intravenous treatment at 3 month intervals
lasting 3 weeks each, during which study medication will be administered daily
over the course of 8 hours. For all 4 courses of treatment patients will be
admitted to the neurology ward of the UMC Utrecht. At Day 1 and 21 of each
treatment cycle patients will undergo a neurological examination, muscle
strength testing, respiratory assessment, laboratory investigations and fill in
questionnaires. Each visit will take approximately two-three hours and beside a
blood draw patients will not experience any discomfort. The main risks
associated with penicillin are seen in patients with penicillin allergy or
those with bacterial infections. Patients with either of these conditions will
not be permitted to participate. Short courses of hydrocortisone are generally
well-tolerated and if side effects do occur they subside after treatment is
discontinued. In this study hydrocortisone will be given for 2 weeks during
each treatment course. All side effects can be effectively managed by any
physician in accordance with standard practices. Therefore the risks of the
study medication appear to be acceptable. The limited clinical findings
reported in the literature suggest that ALS patient may stabilize or even
improve in response to this treatment, in what is now a relentlessly
progressive and fatal neurodegenerative disease. Therefore potential benefits
outweigh the potential risks for this study.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
1. Patients must be over 18 years of age.
2. Patients diagnosed with laboratory supported, clinically probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria (Brooks, 1994).
3. Disease duration from symptoms onset no longer than 24 months at the screening visit.
4. Patient with a FVC (Forced Vital Capacity) equal to or more than 80% predicted normal value for gender, height, and age at the screening visit
5. Patients must have bulbar involvement (defined as clinically evident dysarthria or a >=1 point drop on questions 1-3 of the revised version of the ALS functional rating scale (ALS-FRS-R).
6. Patient treated with a stable dose of riluzole (100 mg/day) for at least 30 days prior to screening.
Exclusion criteria
1. Patients with concomitant frontotemporal dementia (FTD).
2. Patients who underwent gastrostomy.
3. Patients with syphilis or a medical history of syphilis.
4. Patients with known penicillin allergy or patients with a positive penicillin allergy skin test.
5. Patients with a contra-indication for using penicillin (use of methotrexate, renal insufficiency).
6. Patients with a medical history of epilepsy.
7. Patients with a contra-indication for using hydrocortisone (uncontrolled hypertension or diabetes mellitus, ulcus ventriculi or ulcus duodeni, patients with acute infections)
8. In the case of a female with childbearing potential, the patient must not be pregnant or breast-feeding. Women of childbearing potential should use adequate contraception.
9. Patients with a concomitant infection.
10.Patients currently treated with corticosteroids.
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 | EUCTR2017-001983-39-NL |
| CCMO | NL61931.041.17 |