Difference between revisions of "Plan for an Integral Clinical Trial"

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| [[Glutamate|Glutamate toxicity]] ||  ||  || [[Acetyl L-carnitine (ALCAR)]], [[Alcohol]], [[Inosine]], [[Magnesium]], [[Methylcobalamin]], [[Pycnogenol]], [[R Alpha Lipoic Acid (R-ALA)]], Riluzole
 
| [[Glutamate|Glutamate toxicity]] ||  ||  || [[Acetyl L-carnitine (ALCAR)]], [[Alcohol]], [[Inosine]], [[Magnesium]], [[Methylcobalamin]], [[Pycnogenol]], [[R Alpha Lipoic Acid (R-ALA)]], Riluzole
 
|-
 
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| [[Hsp70|Heat shock protein inducers]] ||  ||  || [[Curcumin]], [[Peony root extract]]
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| [[HSF1|Heat shock protein inducers]] ||  ||  || [[Curcumin]], [[Peony root extract]]
  
 
|}
 
|}
  
 
== References ==
 
== References ==

Revision as of 19:12, 10 August 2017

A number of substances have been trialed individually for ALS, and some of them have shown preliminary results that warrant further studies. Even more of them have a plausible mechanism but no clinical results. Although ALS is a collection of diverse diseases, it is possible to recognize several characteristic parameters or processes, manipulation of which would probably be beneficial to majority of PALS.

The aim of this exercise is to propose a "cocktail" consisting of several substances that can be tested integrally in order to see if they have a combined measurable effect on ALS progression.


Selection of Substances

General Criteria

The substances to be included in the cocktail should either be available as over-tnhe-counter products or prescribing them off label should be straightforward. In addition, they need to fulfil at least one of the following criteria:

  1. preliminary signs of efficacy in a human trial
  2. validated effect on a parameter or process that can be estimated to decelerate disease progression in a majority of ALS patients

Selection by Trial Results

Selection by Processes

The basis of this section is the page Supplements listed by their effects


Process/Parameter How common in ALS? Effect of Manipulation Candidate Substances
Neuroinflammation General Reduction is probably beneficial; M2 state of microglia should be promoted. 3nB, Baicalin, Curcumin, Ibuprofen, Luteolin,Magnolia bark extract, Peony root extract, Spirulina, Trimethylglycine, Vitamin D3
Mitochondrial dysfunction Acetyl L-carnitine (ALCAR), European milk thistle extract, MitoQ, PQQ, R Alpha Lipoic Acid (R-ALA), Ubiquinol
Glutamate toxicity Acetyl L-carnitine (ALCAR), Alcohol, Inosine, Magnesium, Methylcobalamin, Pycnogenol, R Alpha Lipoic Acid (R-ALA), Riluzole
Heat shock protein inducers Curcumin, Peony root extract

References

  1. Beghi et al.: Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS. Amyotroph Lateral Scler Frontotemporal Degener 2013;14:397-405. PMID: 23421600. DOI. Our objective was to assess the effects of acetyl-L-carnitine (ALC) with riluzole on disability and mortality of amyotrophic lateral sclerosis (ALS). Definite/probable ALS patients, 40-70 years of age, duration 6-24 months, self-sufficient (i.e. able to swallow, cut food/handle utensils, and walk), and with forced vital capacity (FVC) > 80% entered a pilot double-blind, placebo-controlled, parallel group trial and were followed for 48 weeks. ALC or placebo 3 g/day was added to riluzole 100 mg/day. Primary endpoint: number of patients no longer self-sufficient. Secondary endpoints: changes in ALSFRS-R, MRC, FVC and McGill Quality of Life (QoL) scores. Analysis was made in the intention-to-treat (ITT) and per-protocol (PP) population, completers and completers/compliers (i.e. taking > 75% of study drug). Forty-two patients received ALC and 40 placebo. In the ITT population, 34 (80.9%) patients receiving ALC and 39 (97.5%) receiving placebo became non-self-sufficient (p = 0.0296). In the PP analysis, percentages were 84.4 and 100.0% (p = 0.0538), respectively. Mean ALSFRS-R scores at 48 weeks were 33.6 (SD 10.4) and 27.6 (9.9) (p = 0.0388), respectively, and mean FVC scores 90.3 (32.6) and 58.6 (31.2) (p = 0.0158), respectively. Median survival was 45 months (ALC) and 22 months (placebo) (p = 0.0176). MRC, QoL and adverse events were similar. In conclusion, ALC may be effective, well-tolerated and safe in ALS. A pivotal phase III trial is needed.
  2. Elia et al.: Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur. J. Neurol. 2016;23:45-52. PMID: 25664595. DOI. BACKGROUND AND PURPOSE: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). METHODS: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. RESULTS: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). CONCLUSIONS: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.
  3. Boll et al.: Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis. J. Neurol. Sci. 2014;340:103-8. PMID: 24667005. DOI. The aim of this study was to evaluate the ability of lithium carbonate and valproate cotreatment to modify the survival rate and functional score of patients with definite sporadic amyotrophic lateral sclerosis (ALS). The clinical response of 18 enrolled patients was compared to the evolution of 31 ALS out-patients, carefully paired by age, gender, evolution rate and time of the disease, who never received treatment with lithium and/or valproate. The ALS functional rating scale, revised version (ALSFRS-R), was applied at baseline, 1 month, and every 4 months until the outcome (death or an adverse event). Biochemical markers, such as Cu/Zn superoxide dismutase and glutathione peroxidase activity, and reduced glutathione were assayed in plasma samples obtained at the baseline visit and after 5 and 9 months of treatment. Our results showed that lithium and valproate cotreatment significantly increased survival (p=0.016), and this treatment also exerted neuroprotection in our patients because all three markers reached levels that were not significantly different from the matched samples of healthy donors. The trial stopped after 21 months, when the sample was reduced to under two-thirds, due to the late adverse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events.