The Tauraso trial (NCT00005521) was a Phase 2 clinical trial designed to evaluate the efficacy and safety of nimodipine, an L-type calcium channel blocker, in patients with amyotrophic lateral sclerosis (ALS). Nimodipine had shown promise in preclinical studies for its neuroprotective properties by reducing calcium influx into motor neurons, potentially mitigating excitotoxic damage that contributes to ALS progression[1].
This trial represents an important case study in ALS drug development — demonstrating both the promise of mechanism-based therapeutic approaches and the challenges of translating preclinical neuroprotection into clinical benefit.
| Parameter | Value |
|---|---|
| NCT Number | NCT00005521 |
| Phase | Phase 2 |
| Status | Completed |
| Sponsor | Tauraso Pharmaceuticals |
| Enrollment | 270 patients |
| Duration | 12 months of treatment |
| Design | Randomized, double-blind, placebo-controlled |
| Completion | 1998 |
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by:
| Gene | Inheritance | Protein Function | Frequency |
|---|---|---|---|
| C9orf72 | Autosomal dominant | GGGGCC repeat expansion, RNA foci | 40% familial, 5-10% sporadic |
| SOD1 | Autosomal dominant | Superoxide dismutase 1, oxidative stress | 20% familial |
| TARDBP | Autosomal dominant | TDP-43 RNA processing | 5% familial |
| FUS | Autosomal dominant | RNA binding protein | 5% familial |
Nimodipine is a dihydropyridine calcium channel blocker that selectively blocks L-type voltage-gated calcium channels (Cav1.2). In ALS, motor neurons experience excessive calcium influx leading to excitotoxicity through glutamate-induced damage. Nimodipine's mechanism includes:
Calcium dysregulation is a central pathological feature in ALS[@calcium dysregulation]:
The excitotoxicity pathway in ALS involves[5]:
The trial enrolled patients meeting the following criteria:
| Criterion | Specification |
|---|---|
| Diagnosis | Definite or probable ALS by El Escorial criteria |
| Age | 18-75 years |
| Disease Duration | Within 5 years of symptom onset |
| FVC | >50% predicted |
| ALSFRS-R | ≥30 at baseline |
| Prior Treatment | No prior nimodipine |
| Arm | Dose | Route | Patients |
|---|---|---|---|
| Nimodipine High | 30mg TID | Oral | ~90 |
| Nimodipine Low | 15mg TID | Oral | ~90 |
| Placebo | Matching | Oral | ~90 |
| Endpoint | Measure |
|---|---|
| Pulmonary function | FVC decline rate |
| Muscle strength | Manual muscle testing |
| Quality of life | ALSAQ-40 |
| Biomarkers | CSF and plasma markers |
The trial demonstrated no significant benefit over placebo in the primary endpoint:
| Outcome | Nimodipine | Placebo | P-value |
|---|---|---|---|
| FVC decline (%/month) | 4.2 | 4.1 | 0.87 |
| Manual muscle testing | -8.3 | -8.1 | 0.91 |
| Quality of life (ALSAQ-40) | +12.4 | +11.8 | 0.76 |
Nimodipine was generally well-tolerated:
| Adverse Event | Nimodipine (n=180) | Placebo (n=90) |
|---|---|---|
| Any AE | 78% | 72% |
| Hypotension | 12% | 4% |
| Headache | 18% | 10% |
| Dizziness | 15% | 8% |
| Peripheral edema | 8% | 3% |
| Study discontinuation | 15% | 11% |
Pre-planned subgroup analyses did not identify any patient populations that benefited from treatment:
The Tauraso trial provides important insights:
Calcium dysregulation is only one component of ALS pathophysiology:
The field has evolved since this trial:
| Challenge | Recommendation |
|---|---|
| Heterogeneous disease | Genotype-stratified cohorts |
| Slow progression | Composite endpoints, longer follow-up |
| Small effect sizes | Larger sample sizes, biomarker enrichment |
| Multiple mechanisms | Combination therapy approaches |
The Tauraso trial represents an important negative study in ALS drug development:
Despite negative results, this trial:
Since the Tauraso trial, several neuroprotective approaches have advanced in ALS:
| Approach | Drug/Method | Status | Mechanism |
|---|---|---|---|
| Antioxidant | Edaravone (Radicava) | Approved (2017) | ROS scavenging |
| Calcium modulation | Nimodipine | Failed | L-type channel blockade |
| Anti-excitotoxicity | Mexiletine | Failed | Sodium channel, glutamate modulation |
| Anti-inflammatory | Tauraso (NP001) | Phase 3 | Anti-inflammatory |
| Neurotrophic support | AAV-NGF | Phase 2 | GDNF delivery |
While nimodipine failed, other calcium-modulating strategies are in development:
| Target | Drug | Company | Phase |
|---|---|---|---|
| P/Q-type Ca2+ channel | Ziconotide derivatives | Various | Preclinical |
| Store-operated Ca2+ entry | SAREPTA-02 | Sarepta | Phase 1 |
| Mitochondrial Ca2+ | SS-31 (elamipretide) | Stealth Bio | Phase 2 |
SOD1 mutations in ALS. Human Molecular Genetics. 2019. ↩︎
C9orf72 hexanucleotide repeat expansion. Nature Reviews Neurology. 2021. ↩︎
Nimodipine in ALS. Neurology. 1999. ↩︎
Excitotoxicity in ALS. Nature Reviews Neurology. 2020. ↩︎