Impact of the Combined Treatment of Liposomed Polyphenols With G04CB02 on the ALS Patients
NCT ID: NCT04654689
Last Updated: 2025-10-08
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE2
Total Enrollment
90 participants
Study Classification
INTERVENTIONAL
Study Start Date
2021-11-20
Study Completion Date
2023-02-04
Brief Summary
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Amyotrophic lateral sclerosis (ALS) is a disease of an inflammatory nature, which causes progressive muscle weakness associated with cognitive and behavioural disorders. Pathogenically, it is characterised by loss of oxidative control, excitotoxicity due to excess glutamate and intestinal dysbiosis. In the absence of curative treatment, the aim of the study is to assess the impact at a clinical level of the combination of liposomed polyphenols to improve their effectiveness, with the drug G04CB02 which shows great anti-ALS properties by Molecular Topology methodology. A prospective, longitudinal, mixed, analytical, experimental and double-blind study is proposed, with a population sample of 60 patients distributed randomly in 30 patients in the intervention group who will receive treatment for 2 months, and 30 patients in the control group who will receive a placebo for the same period. The assessment will be at time 0, and at 2 months and 4 months after treatment, with functional, cognitive and behavioural tests, and of the state of inflammation and oxidation; and at time 0 and 2 months, of the intestinal microbiota.
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Detailed Description
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Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of an inflammatory nature among those affecting motor neurons, with a life expectancy of 3 to 5 years. It is characterised by the loss of motor neurons, and can be of the bulbar type when the pathology begins to affect the motor neurons located in the spinal bulb, or of the medullary type when it begins with a loss of strength and weakness in the extremities. Both types eventually lead to an affectation of both motor neurons that results in progressive paralysis of the voluntary muscles until the patient dies. In addition, the pathology presents cognitive and behavioural alterations. Specifically, deficits have been described in verbal fluency, memory, emotional processing or social cognition, which appear to be mainly associated with hypoperfusion of the prefrontal area or hypometabolism.
Pathogenically, ALS is characterised by an alteration in mitochondrial energy use at a neuronal level, mainly linked to a lower activity of the enzymes of the electron transport chain in the spinal cord. This alteration is a consequence of loss of oxidative control, excessive generation of oxidative free radicals, accumulation of neurofilaments, and excitotoxicity linked to an increase in the neurotransmitter glutamate.
In this respect, it has been suggested that bacterial dysbiosis, related to cognitive and behavioural worsening, could also contribute to this adverse neuroinflammatory state, having been associated with a greater risk of suffering from neurodegenerative diseases. Specifically in ALS, a variation in intestinal microbial composition has recently been observed, with an increased abundance of E. coli and enterobacteria, and a low abundance of total yeast, in patients suffering from ALS; and lower levels of non-butyrate producing bacteria needed to maintain the integrity of the intestinal barrier, immune competition and energy metabolism. In contrast, increased Akkermansia muciniphila has been associated with higher levels of nicotinamide and improved disease symptoms in the animal model of the disease.
This evidence, associated with the lack of medical treatment to cure the disease, makes it necessary to look for new therapeutic alternatives of a non-pharmacological nature. These include the administration of effective antioxidants, which reverse the high oxidative stress and inflammation characteristic of the disease. This type of treatment (specifically the association of the antioxidants Pterostilbene and Nicotinamide riboside) has already been applied by our research group to patients with ALS, achieving significant clinical improvements such as: greater functional capacity, greater respiratory capacity, increased muscle strength and electrical activity in the upper and lower limbs, as well as an increase in the percentage of skeletal muscle associated with fat loss. In this sense, several polyphenols have also been tested in animal models, among which the activity shown by Resveratrol stands out, with a high antioxidant power and great neuroprotective capacity, which is associated with an increase in the expression and activation of SIRT1 and AMPK in the ventral part of the spinal cord after its administration. Both mediators promoted the normalization of autophage flow and, more importantly, increased mitochondrial biogenesis in SOD1-G93A mice. However, their beneficial effects are strongly limited by their low availability. This limitation can be overcome by administering Resveratrol and its natural analogues, incorporated in liposomes or nanoparticles, as this is the best option for guaranteeing stability and bioavailability, after administration and absorption of the antioxidant.
Moreover, the effects of the polyphenol Curcumin have already been studied in ALS. In a paper by Chico et al, its effects were studied in ALS patients at doses of 600mg/day for 6 months. In this study they found that Curcumin generated a slight slowdown in the progression of the disease, improving aerobic metabolism and oxidative damage. Furthermore, the use of nanobiotechnology with Curcumin (80mg/day) in the treatment of ALS patients obtained positive results showing that nanocurcumin is safe and could improve the probability of survival as an additional treatment in these patients, especially those with existing bulbar symptoms. In short, the use of both antioxidants in liposome form improves the bioavailability and effects of both, and their liposome combination has already been successfully tested in vivo in prostate cancer patients.
These anti-ALS effects of the two molecules could be complemented by their action in improving the microbiota. To obtain the bioactive products of Curcumin, biotransformation by the human intestinal microflora is necessary; in a bidirectional manner, it has been demonstrated that Curcumin has beneficial effects on the intestinal microbiota by increasing the number of bacterial families such as: Prevotellaceae, Bifidobacterium, Lactobacilli, Bacteroidaceae and Rikenellaceae, and reducing the number of pro-inflammatory bacterial families such as: Enterobacteria and Enterococci. With regard to Resveratrol, as occurs with Curcumin, the intestinal microflora contributes to its metabolism; and also stands out in the increased production of anti-inflammatory bacteria of the Lactobacillus or Bifidobacterium genera. In addition, it has been found to increase levels of the bacterium Akkermansia Muciniphila, which is associated with an improvement in the prognosis of the disease.
Finally, the use of these two antioxidants in ALS would be combined synergistically by repositioning G04CB02, a drug selected after a molecular topology scan of more than 30,000 drugs from two databases: CMC and Drugbank. It is currently marketed for the treatment of different pathologies, such as benign prostatic hyperplasia and androgenic alopecia. According to the in silico studies based on Molecular Topology carried out by Dr. Gálvez's team, a very promising anti-ALS effect has been identified for G04CB02, linked to the TDP-43 RNA mediator, among others. Drug design using molecular topology consists of applying topological descriptors to identify and describe, using a specific mathematical pattern, molecules and/or drugs related to a specific disease, in this case ALS. Using molecules with proven anti-ALS activity (Edaravone and Riluzole) and the TDP-43 RNA mediator, this mathematical pattern was identified and the databases mentioned above were traced with the aim of identifying drugs that share the same pattern and therefore have potential anti-ALS activity. In addition, considering the current shortage of effective treatments for ALS, other mathematical patterns related to anti-inflammatory, antioxidant, neuroprotective and analgesic activity were taken into account when selecting the G04CB02 candidate. To date, molecular topology has enabled the identification of new treatments for CNS diseases such as Alzheimer's, cancer and very recently SARS-Cov-2, among others.
Pathogenically, ALS is characterised by an alteration in mitochondrial energy use at a neuronal level, mainly linked to a lower activity of the enzymes of the electron transport chain in the spinal cord. This alteration is a consequence of loss of oxidative control, excessive generation of oxidative free radicals, accumulation of neurofilaments, and excitotoxicity linked to an increase in the neurotransmitter glutamate.
In this respect, it has been suggested that bacterial dysbiosis, related to cognitive and behavioural worsening, could also contribute to this adverse neuroinflammatory state, having been associated with a greater risk of suffering from neurodegenerative diseases. Specifically in ALS, a variation in intestinal microbial composition has recently been observed, with an increased abundance of E. coli and enterobacteria, and a low abundance of total yeast, in patients suffering from ALS; and lower levels of non-butyrate producing bacteria needed to maintain the integrity of the intestinal barrier, immune competition and energy metabolism. In contrast, increased Akkermansia muciniphila has been associated with higher levels of nicotinamide and improved disease symptoms in the animal model of the disease.
This evidence, associated with the lack of medical treatment to cure the disease, makes it necessary to look for new therapeutic alternatives of a non-pharmacological nature. These include the administration of effective antioxidants, which reverse the high oxidative stress and inflammation characteristic of the disease. This type of treatment (specifically the association of the antioxidants Pterostilbene and Nicotinamide riboside) has already been applied by our research group to patients with ALS, achieving significant clinical improvements such as: greater functional capacity, greater respiratory capacity, increased muscle strength and electrical activity in the upper and lower limbs, as well as an increase in the percentage of skeletal muscle associated with fat loss. In this sense, several polyphenols have also been tested in animal models, among which the activity shown by Resveratrol stands out, with a high antioxidant power and great neuroprotective capacity, which is associated with an increase in the expression and activation of SIRT1 and AMPK in the ventral part of the spinal cord after its administration. Both mediators promoted the normalization of autophage flow and, more importantly, increased mitochondrial biogenesis in SOD1-G93A mice. However, their beneficial effects are strongly limited by their low availability. This limitation can be overcome by administering Resveratrol and its natural analogues, incorporated in liposomes or nanoparticles, as this is the best option for guaranteeing stability and bioavailability, after administration and absorption of the antioxidant.
Moreover, the effects of the polyphenol Curcumin have already been studied in ALS. In a paper by Chico et al, its effects were studied in ALS patients at doses of 600mg/day for 6 months. In this study they found that Curcumin generated a slight slowdown in the progression of the disease, improving aerobic metabolism and oxidative damage. Furthermore, the use of nanobiotechnology with Curcumin (80mg/day) in the treatment of ALS patients obtained positive results showing that nanocurcumin is safe and could improve the probability of survival as an additional treatment in these patients, especially those with existing bulbar symptoms. In short, the use of both antioxidants in liposome form improves the bioavailability and effects of both, and their liposome combination has already been successfully tested in vivo in prostate cancer patients.
These anti-ALS effects of the two molecules could be complemented by their action in improving the microbiota. To obtain the bioactive products of Curcumin, biotransformation by the human intestinal microflora is necessary; in a bidirectional manner, it has been demonstrated that Curcumin has beneficial effects on the intestinal microbiota by increasing the number of bacterial families such as: Prevotellaceae, Bifidobacterium, Lactobacilli, Bacteroidaceae and Rikenellaceae, and reducing the number of pro-inflammatory bacterial families such as: Enterobacteria and Enterococci. With regard to Resveratrol, as occurs with Curcumin, the intestinal microflora contributes to its metabolism; and also stands out in the increased production of anti-inflammatory bacteria of the Lactobacillus or Bifidobacterium genera. In addition, it has been found to increase levels of the bacterium Akkermansia Muciniphila, which is associated with an improvement in the prognosis of the disease.
Finally, the use of these two antioxidants in ALS would be combined synergistically by repositioning G04CB02, a drug selected after a molecular topology scan of more than 30,000 drugs from two databases: CMC and Drugbank. It is currently marketed for the treatment of different pathologies, such as benign prostatic hyperplasia and androgenic alopecia. According to the in silico studies based on Molecular Topology carried out by Dr. Gálvez's team, a very promising anti-ALS effect has been identified for G04CB02, linked to the TDP-43 RNA mediator, among others. Drug design using molecular topology consists of applying topological descriptors to identify and describe, using a specific mathematical pattern, molecules and/or drugs related to a specific disease, in this case ALS. Using molecules with proven anti-ALS activity (Edaravone and Riluzole) and the TDP-43 RNA mediator, this mathematical pattern was identified and the databases mentioned above were traced with the aim of identifying drugs that share the same pattern and therefore have potential anti-ALS activity. In addition, considering the current shortage of effective treatments for ALS, other mathematical patterns related to anti-inflammatory, antioxidant, neuroprotective and analgesic activity were taken into account when selecting the G04CB02 candidate. To date, molecular topology has enabled the identification of new treatments for CNS diseases such as Alzheimer's, cancer and very recently SARS-Cov-2, among others.
Conditions
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Amyotrophic Lateral Sclerosis
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
* Intervention group: 30 patients will be administered daily the combination of Resveratrol (75mg) and Curcumin (200mg) liposomes with G04CB02 (0.5mg), in a single dose for 2 months.
* Control group: 30 patients, who will receive a placebo with the same dosage pattern and for the same period of time. The placebo will consist of water with sucrose replacing the liposomed polyphenols, and a soft capsule of microcrystalline methylcellulose instead of G04CB02. Both the packaging and the capsule format will be identical to those of the treatment administered in the intervention group.
* Control group: 30 patients, who will receive a placebo with the same dosage pattern and for the same period of time. The placebo will consist of water with sucrose replacing the liposomed polyphenols, and a soft capsule of microcrystalline methylcellulose instead of G04CB02. Both the packaging and the capsule format will be identical to those of the treatment administered in the intervention group.
Primary Study Purpose
SUPPORTIVE_CARE
Blinding Strategy
TRIPLE
Participants
Caregivers
Investigators
Study Groups
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Intervention group
30 patients will be given the combination of resveratrol and curcumin liposomed with G04CB02, in a single daily dose for 2 months.
Group Type
EXPERIMENTAL
Liposomed polyphenols resveratrol and curcumin
Intervention Type
DIETARY_SUPPLEMENT
Combination of resveratrol (75mg) and curcumin (200mg) liposomed
Isocaloric Diet
Intervention Type
DIETARY_SUPPLEMENT
40% carbohydrates, 40% lipids and 20% proteins
G04CB02
Intervention Type
DRUG
G04CB02, in a single daily dose for 2 months
Control group
30 patients, who will receive a placebo with the same dosage pattern and for the same period of time. The placebo will consist of water with sucrose replacing the liposomal polyphenols, and a soft capsule of microcrystalline methylcellulose instead of G04CB02. Both the packaging and the capsule format will be identical to those of the treatment administered in the intervention group
Group Type
PLACEBO_COMPARATOR
Placebo for liposomed resveratrol and curcumin
Intervention Type
OTHER
Water with sucrose replacing the liposomed polyphenols
Isocaloric Diet
Intervention Type
DIETARY_SUPPLEMENT
40% carbohydrates, 40% lipids and 20% proteins
Placebo microcrystalline methylcellulose
Intervention Type
OTHER
Placebo replacing G04CB02
Interventions
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Liposomed polyphenols resveratrol and curcumin
Combination of resveratrol (75mg) and curcumin (200mg) liposomed
Intervention Type
DIETARY_SUPPLEMENT
Placebo for liposomed resveratrol and curcumin
Water with sucrose replacing the liposomed polyphenols
Intervention Type
OTHER
Isocaloric Diet
40% carbohydrates, 40% lipids and 20% proteins
Intervention Type
DIETARY_SUPPLEMENT
G04CB02
G04CB02, in a single daily dose for 2 months
Intervention Type
DRUG
Placebo microcrystalline methylcellulose
Placebo replacing G04CB02
Intervention Type
OTHER
Eligibility Criteria
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Inclusion Criteria
* All ALS patients, over 18 years of age and with a clear diagnosis and symptomatology of ALS since at least 6 months.
Exclusion Criteria
* Women under 50 years of age and childbearing age.
* Tracheotomy patients.
* Patients with invasive or non-invasive ventilation with positive ventilatory pressure
* Patients with evidence of dementia.
* Patients with alcohol or drug abuse dependency.
* Patients infected with B or C hepatitis, or HIV positive
* Renal patients with creatinine levels twice as high as normal markers.
* Liver patients with liver markers (ALT, AST) elevated 3 times above normal levels.
* Patients included in other research with drugs or therapies in the experimental phase.
* Patients treated with anticoagulants or with haemostatic problems
* Tracheotomy patients.
* Patients with invasive or non-invasive ventilation with positive ventilatory pressure
* Patients with evidence of dementia.
* Patients with alcohol or drug abuse dependency.
* Patients infected with B or C hepatitis, or HIV positive
* Renal patients with creatinine levels twice as high as normal markers.
* Liver patients with liver markers (ALT, AST) elevated 3 times above normal levels.
* Patients included in other research with drugs or therapies in the experimental phase.
* Patients treated with anticoagulants or with haemostatic problems
Minimum Eligible Age
18 Years
Maximum Eligible Age
75 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Fundación Universidad Católica de Valencia San Vicente Mártir
OTHER
Sponsor Role
lead
Responsible Party
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José Enrique de la Rubia Ortí, Ph
Director
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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José Enrique De la Rubia Ortí, Ph
Role: PRINCIPAL_INVESTIGATOR
Catholic University of Valencia
Locations
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José Enrique de la Rubia Ortí
Valencia, Valencia, Spain
Site Status
Countries
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Spain
References
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Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
2020-005143-23
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
UCV/2020-2021/018
Identifier Type: -
Identifier Source: org_study_id
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