Amyotrophic Lateral SclerosisPhase 2NCT04654689
Impact of the Combined Treatment of Liposomed Polyphenols With G04CB02 on the ALS Patients
A Phase 2 study testing Liposomed polyphenols resveratrol and curcumin, Isocaloric Diet and G04CB02 in people with Amyotrophic Lateral Sclerosis, run by Fundación Universidad Católica de Valencia San Vicente Mártir at 1 site in Spain.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Amyotrophic Lateral Sclerosis
- What is being tested?
- Liposomed polyphenols resveratrol and curcumin, Isocaloric Diet and G04CB02
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 90 participants
- Where
- 1 siteSpain
- Study dates
- 8 Jul 2021to 4 Feb 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- All ALS patients, over 18 years of age and with a clear diagnosis and symptomatology of ALS since at least 6 months.
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Impact of the Combined Treatment of Curcumin and Resveratrol Liposomed Polyphenols With G04CB02 on the Clinical Improvement of ALS Patients
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.
Read the detailed description
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.
- Conditions
- Amyotrophic Lateral Sclerosis
- Being tested
- Liposomed polyphenols resveratrol and curcumin, Placebo for liposomed resveratrol and curcumin, Isocaloric Diet, G04CB02, Placebo microcrystalline methylcellulose
- Medical subject headings
- Amyotrophic Lateral Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Liposomed polyphenols resveratrol and curcuminDietary supplement
Combination of resveratrol (75mg) and curcumin (200mg) liposomed
Placebo for liposomed resveratrol and curcuminOther
Water with sucrose replacing the liposomed polyphenols
Isocaloric DietDietary supplement
40% carbohydrates, 40% lipids and 20% proteins
G04CB02Drug
G04CB02, in a single daily dose for 2 months
Placebo microcrystalline methylcelluloseOther
Placebo replacing G04CB02
| Study group | Role | What they receive |
|---|---|---|
| Intervention group | Experimental | 30 patients will be given the combination of resveratrol and curcumin liposomed with G04CB02, in a single daily dose for 2 months. Receives: Dietary Supplement: Liposomed polyphenols resveratrol and curcumin; Dietary Supplement: Isocaloric Diet; Drug: G04CB02 |
| Control group | Placebo comparator | 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 Receives: Other: Placebo for liposomed resveratrol and curcumin; Dietary Supplement: Isocaloric Diet; Other: Placebo microcrystalline methylcellulose |
What is being measured
The primary outcome is the main question the study is designed to answer.
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale associated with ALS
Maximum value: 48 points; Means better outcome motor variables Minimum value: 0 points
Measured: Time 0
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale associated with ALS
Maximum value: 48 points; Means better outcome motor variables Minimum value: 0 points
Measured: 2 months
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale associated with ALS
Maximum value: 48 points; Means better outcome motor variables Minimum value: 0 points
Measured: 4 months
Electromyography
Motor Variables
Measured: Time 0
Electromyography
Motor Variables
Measured: 2 months
Electromyography
Motor Variables
Measured: 4 months
Measurement of forced vital capacity
Motor Variables
Measured: Time 0
Measurement of forced vital capacity
Motor Variables
Measured: 2 months
Measurement of forced vital capacity
Motor Variables
Measured: 4 months
Secondary outcomes (24)
Quantitative measurement of plasma IL-6 and TNF-alpha.
Variables related to inflammation and oxidation
Measured: Time 0
Quantitative measurement of plasma IL-6 and TNF-alpha.
Variables related to inflammation and oxidation
Measured: 2 months
Quantitative measurement of plasma IL-6 and TNF-alpha.
Variables related to inflammation and oxidation
Measured: 4 months
Quantitative measurement of plasma PCR.
Variables related to inflammation and oxidation
Measured: Time 0
Quantitative measurement of plasma PCR.
Variables related to inflammation and oxidation
Measured: 2 months
Quantitative measurement of plasma PCR.
Variables related to inflammation and oxidation
Measured: 4 months
Quantitative measurement of plasma haptoglobin.
Variables related to inflammation and oxidation
Measured: Time 0
Quantitative measurement of plasma haptoglobin.
Variables related to inflammation and oxidation
Measured: 2 months
Quantitative measurement of plasma haptoglobin.
Variables related to inflammation and oxidation
Measured: 4 months
Quantitative measurement of TEAC (oxidation).
Variables related to inflammation and oxidation
Measured: Time 0
Quantitative measurement of TEAC (oxidation).
Variables related to inflammation and oxidation
Measured: 2 months
Quantitative measurement of TEAC (oxidation).
Variables related to inflammation and oxidation
Measured: 4 months
Quantitative measurement of plasma 8-oxoG.
Variables related to inflammation and oxidation
Measured: Time 0
Quantitative measurement of plasma 8-oxoG.
Variables related to inflammation and oxidation
Measured: 2 months
Quantitative measurement of plasma 8-oxoG.
Variables related to inflammation and oxidation
Measured: 4 months
Quantitative measurement of plasma MDA.
Variables related to inflammation and oxidation
Measured: Time 0
Quantitative measurement of plasma MDA.
Variables related to inflammation and oxidation
Measured: 2 months
Quantitative measurement of plasma MDA.
Variables related to inflammation and oxidation
Measured: 4 months
Edinburgh Cognitive and Behavioral ALS Screen
Variable for cognitive and behavioural assesment
Maximum value: 136 points; Means better outcome Minimum value: 0 points
Includes a behavioural test to interview the care provider
Measured: Time 0
Edinburgh Cognitive and Behavioral ALS Screen
Variable for cognitive and behavioural assesment
Maximum value: 136 points; Means better outcome Minimum value: 0 points
Includes a behavioural test to interview the care provider
Measured: 2 months
Edinburgh Cognitive and Behavioral ALS Screen
Variable for cognitive and behavioural assesment
Maximum value: 136 points; Means better outcome Minimum value: 0 points
Includes a behavioural test to interview the care provider
Measured: 4 months
Frontal Assessment Battery
Variable for cognitive and behavioural assesment
Maximum value: 18 points; Means better outcome 16-15 points means frontosubcortical deficit 13-12 points means frontosubcortical dementia Minimum value: 0 points
Includes a behavioural test to interview the care provider
Measured: Time 0
Frontal Assessment Battery
Variable for cognitive and behavioural assesment
Maximum value: 18 points; Means better outcome 16-15 points means frontosubcortical deficit 13-12 points means frontosubcortical dementia Minimum value: 0 points
Includes a behavioural test to interview the care provider
Measured: 2 months
Frontal Assessment Battery
Variable for cognitive and behavioural assesment
Maximum value: 18 points; Means better outcome 16-15 points means frontosubcortical deficit 13-12 points means frontosubcortical dementia Minimum value: 0 points
Includes a behavioural test to interview the care provider
Measured: 4 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2020
- Study start8 Jul 2021
- Primary completion12 Nov 2022
- Study completion4 Feb 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (54)Papers the sponsor has linked to this study.
- Other trials for Amyotrophic Lateral SclerosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- * 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.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 90 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fundación Universidad Católica de Valencia San Vicente Mártir
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, José Enrique de la Rubia Ortí, Ph, Fundación Universidad Católica de Valencia San Vicente Mártir
- Investigators
- José Enrique De la Rubia Ortí, Ph, Principal investigator, Catholic University of Valencia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04654689
- Sponsor's protocol ID
- UCV/2020-2021/018
- Other IDs
- 2021-001989-38
- Status last verified
- Oct 2026
- First submitted
- 13 Nov 2020
- Last updated
- 19 Oct 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Variables related to inflammation and oxidation: * Quantitative measurement of plasma IL-6 and TNF-alpha. * Quantitative measurement of plasma PCR. * Quantitative measurement of plasma haptoglobin. * Quantitative measurement of TEAC (oxidation). * Quantitative measurement of plasma 8-oxoG. * Quantitative measurement of plasma MDA. Variables for cognitive and behavioural assessment: * Edinburgh Cognitive and Behavioral ALS Screen * Frontal Assessment Battery (FAB)
Publications
Riancho J, Gonzalo I, Ruiz-Soto M, Berciano J. Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis. Neurologia (Engl Ed). 2019 Jan-Feb;34(1):27-37. doi: 10.1016/j.nrl.2015.12.001. Epub 2016 Feb 4. English, Spanish.
PubMed 26853842Gordon PH. Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials. Aging Dis. 2013 Oct 1;4(5):295-310. doi: 10.14336/AD.2013.0400295.
PubMed 24124634Woolley SC, Jonathan S Katz. Cognitive and behavioral impairment in amyotrophic lateral sclerosis. Phys Med Rehabil Clin N Am. 2008 Aug;19(3):607-17, xi. doi: 10.1016/j.pmr.2008.04.002.
PubMed 18625419Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 2007 Nov;6(11):994-1003. doi: 10.1016/S1474-4422(07)70265-X.
PubMed 17945153Ralli M, Lambiase A, Artico M, de Vincentiis M, Greco A. Amyotrophic Lateral Sclerosis: Autoimmune Pathogenic Mechanisms, Clinical Features, and Therapeutic Perspectives. Isr Med Assoc J. 2019 Jul;21(7):438-443.
PubMed 31507117Ticinesi A, Nouvenne A, Tana C, Prati B, Meschi T. Gut Microbiota and Microbiota-Related Metabolites as Possible Biomarkers of Cognitive Aging. Adv Exp Med Biol. 2019;1178:129-154. doi: 10.1007/978-3-030-25650-0_8.
PubMed 31493226Alifirova VM, Zhukova NG, Zhukova IA, Mironova YS, Petrov VA, Izhboldina OP, Titova MA, Latypova AV, Nikitina MA, Dorofeeva YB, Saltykova IV, Tyakht AV, Kostryukova ES, Sazonov AE. [Correlation Between Emotional-Affective Disorders and Gut Microbiota Composition in Patients with Parkinson's Disease]. Vestn Ross Akad Med Nauk. 2016;71(6):427-35. doi: 10.15690/vramn734. Russian.
PubMed 29298003Spielman LJ, Gibson DL, Klegeris A. Unhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases. Neurochem Int. 2018 Nov;120:149-163. doi: 10.1016/j.neuint.2018.08.005. Epub 2018 Aug 14.
PubMed 30114473Roy Sarkar S, Banerjee S. Gut microbiota in neurodegenerative disorders. J Neuroimmunol. 2019 Mar 15;328:98-104. doi: 10.1016/j.jneuroim.2019.01.004. Epub 2019 Jan 9.
PubMed 30658292Mazzini L, Mogna L, De Marchi F, Amoruso A, Pane M, Aloisio I, Cionci NB, Gaggia F, Lucenti A, Bersano E, Cantello R, Di Gioia D, Mogna G. Potential Role of Gut Microbiota in ALS Pathogenesis and Possible Novel Therapeutic Strategies. J Clin Gastroenterol. 2018 Nov/Dec;52 Suppl 1, Proceedings from the 9th Probiotics, Prebiotics and New Foods, Nutraceuticals and Botanicals for Nutrition & Human and Microbiota Health Meeting, held in Rome, Italy from September 10 to 12, 2017:S68-S70. doi: 10.1097/MCG.0000000000001042.
PubMed 29782468Wright ML, Fournier C, Houser MC, Tansey M, Glass J, Hertzberg VS. Potential Role of the Gut Microbiome in ALS: A Systematic Review. Biol Res Nurs. 2018 Oct;20(5):513-521. doi: 10.1177/1099800418784202. Epub 2018 Jun 20.
PubMed 29925252Erber AC, Cetin H, Berry D, Schernhammer ES. The role of gut microbiota, butyrate and proton pump inhibitors in amyotrophic lateral sclerosis: a systematic review. Int J Neurosci. 2020 Jul;130(7):727-735. doi: 10.1080/00207454.2019.1702549. Epub 2019 Dec 23.
PubMed 31870202Blacher E, Bashiardes S, Shapiro H, Rothschild D, Mor U, Dori-Bachash M, Kleimeyer C, Moresi C, Harnik Y, Zur M, Zabari M, Brik RB, Kviatcovsky D, Zmora N, Cohen Y, Bar N, Levi I, Amar N, Mehlman T, Brandis A, Biton I, Kuperman Y, Tsoory M, Alfahel L, Harmelin A, Schwartz M, Israelson A, Arike L, Johansson MEV, Hansson GC, Gotkine M, Segal E, Elinav E. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature. 2019 Aug;572(7770):474-480. doi: 10.1038/s41586-019-1443-5. Epub 2019 Jul 22.
PubMed 31330533de la Rubia JE, Drehmer E, Platero JL, Benlloch M, Caplliure-Llopis J, Villaron-Casales C, de Bernardo N, AlarcOn J, Fuente C, Carrera S, Sancho D, GarcIa-Pardo P, Pascual R, JuArez M, Cuerda-Ballester M, Forner A, Sancho-Castillo S, Barrios C, Obrador E, Marchio P, Salvador R, Holmes HE, Dellinger RW, Guarente L, Estrela JM. Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study. Amyotroph Lateral Scler Frontotemporal Degener. 2019 Feb;20(1-2):115-122. doi: 10.1080/21678421.2018.1536152. Epub 2019 Jan 22.
PubMed 30668199Song W, Song Y, Kincaid B, Bossy B, Bossy-Wetzel E. Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: neuroprotection by SIRT3 and PGC-1alpha. Neurobiol Dis. 2013 Mar;51:72-81. doi: 10.1016/j.nbd.2012.07.004. Epub 2012 Jul 20.
PubMed 22819776
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of the Combined Treatment of Curcumin and Resveratrol Liposomed Polyphenols With G04CB02 on the Clinical Improvement of ALS Patients
- ClinicalTrials.gov ID
- NCT04654689
- Acronym / sponsor ID
- UCV/2020-2021/018
- Conditions
- Amyotrophic Lateral Sclerosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 90 participants (actual)
- Lead sponsor
- Fundación Universidad Católica de Valencia San Vicente MártirUniversity, hospital or other
- Study start
- 8 Jul 2021 (actual)
- Primary completion
- 12 Nov 2022 (actual)
- Study completion
- 4 Feb 2023 (actual)
- First posted
- 4 Dec 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- * 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.
| Arm | Type | Receives |
|---|---|---|
| Intervention group | Experimental | Dietary Supplement: Liposomed polyphenols resveratrol and curcumin, Dietary Supplement: Isocaloric Diet, Drug: G04CB0230 patients will be given the combination of resveratrol and curcumin liposomed with G04CB02, in a single daily dose for 2 months. |
| Control group | Placebo comparator | Other: Placebo for liposomed resveratrol and curcumin, Dietary Supplement: Isocaloric Diet, Other: Placebo microcrystalline methylcellulose30 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 |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- All ALS patients, over 18 years of age and with a clear diagnosis and symptomatology of ALS since at least 6 months.
Key exclusion criteria (10 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Liposomed polyphenols resveratrol and curcuminCombination of resveratrol (75mg) and curcumin (200mg) liposomed | Dietary supplement | Intervention group |
| Placebo for liposomed resveratrol and curcuminWater with sucrose replacing the liposomed polyphenols | Other | Control group |
| Isocaloric Diet40% carbohydrates, 40% lipids and 20% proteins | Dietary supplement | Control group, Intervention group |
| G04CB02G04CB02, in a single daily dose for 2 months | Drug | Intervention group |
| Placebo microcrystalline methylcellulosePlacebo replacing G04CB02 | Other | Control group |
Primary outcome
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale associated with ALS
Time frame: Time 0
Maximum value: 48 points; Means better outcome motor variables Minimum value: 0 points
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale associated with ALS
Time frame: 2 months
Maximum value: 48 points; Means better outcome motor variables Minimum value: 0 points
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale associated with ALS
Time frame: 4 months
Maximum value: 48 points; Means better outcome motor variables Minimum value: 0 points
Electromyography
Time frame: Time 0
Motor Variables
Electromyography
Time frame: 2 months
Motor Variables
Electromyography
Time frame: 4 months
Motor Variables
Measurement of forced vital capacity
Time frame: Time 0
Motor Variables
Measurement of forced vital capacity
Time frame: 2 months
Motor Variables
Measurement of forced vital capacity
Time frame: 4 months
Motor Variables
24 secondary outcomes
Quantitative measurement of plasma IL-6 and TNF-alpha.
Time frame: Time 0
Quantitative measurement of plasma IL-6 and TNF-alpha.
Time frame: 2 months
Quantitative measurement of plasma IL-6 and TNF-alpha.
Time frame: 4 months
Quantitative measurement of plasma PCR.
Time frame: Time 0
Quantitative measurement of plasma PCR.
Time frame: 2 months
Quantitative measurement of plasma PCR.
Time frame: 4 months
Quantitative measurement of plasma haptoglobin.
Time frame: Time 0
Quantitative measurement of plasma haptoglobin.
Time frame: 2 months
Quantitative measurement of plasma haptoglobin.
Time frame: 4 months
Quantitative measurement of TEAC (oxidation).
Time frame: Time 0
Quantitative measurement of TEAC (oxidation).
Time frame: 2 months
Quantitative measurement of TEAC (oxidation).
Time frame: 4 months
Quantitative measurement of plasma 8-oxoG.
Time frame: Time 0
Quantitative measurement of plasma 8-oxoG.
Time frame: 2 months
Quantitative measurement of plasma 8-oxoG.
Time frame: 4 months
Quantitative measurement of plasma MDA.
Time frame: Time 0
Quantitative measurement of plasma MDA.
Time frame: 2 months
Quantitative measurement of plasma MDA.
Time frame: 4 months
Edinburgh Cognitive and Behavioral ALS Screen
Time frame: Time 0
Edinburgh Cognitive and Behavioral ALS Screen
Time frame: 2 months
Edinburgh Cognitive and Behavioral ALS Screen
Time frame: 4 months
Frontal Assessment Battery
Time frame: Time 0
Frontal Assessment Battery
Time frame: 2 months
Frontal Assessment Battery
Time frame: 4 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2026.
- Background: PubMed 26853842Riancho J, Gonzalo I, Ruiz-Soto M, Berciano J. Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis. Neurologia (Engl Ed). 2019 Jan-Feb;34(1):27-37. doi: 10.1016/j.nrl.2015.12.001. Epub 2016 Feb 4. English, Spanish.
- Background: PubMed 24124634Gordon PH. Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials. Aging Dis. 2013 Oct 1;4(5):295-310. doi: 10.14336/AD.2013.0400295.
- Background: PubMed 18625419Woolley SC, Jonathan S Katz. Cognitive and behavioral impairment in amyotrophic lateral sclerosis. Phys Med Rehabil Clin N Am. 2008 Aug;19(3):607-17, xi. doi: 10.1016/j.pmr.2008.04.002.
- Background: PubMed 17945153Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 2007 Nov;6(11):994-1003. doi: 10.1016/S1474-4422(07)70265-X.
- Background: PubMed 31507117Ralli M, Lambiase A, Artico M, de Vincentiis M, Greco A. Amyotrophic Lateral Sclerosis: Autoimmune Pathogenic Mechanisms, Clinical Features, and Therapeutic Perspectives. Isr Med Assoc J. 2019 Jul;21(7):438-443.
- Background: PubMed 31493226Ticinesi A, Nouvenne A, Tana C, Prati B, Meschi T. Gut Microbiota and Microbiota-Related Metabolites as Possible Biomarkers of Cognitive Aging. Adv Exp Med Biol. 2019;1178:129-154. doi: 10.1007/978-3-030-25650-0_8.
- Background: PubMed 29298003Alifirova VM, Zhukova NG, Zhukova IA, Mironova YS, Petrov VA, Izhboldina OP, Titova MA, Latypova AV, Nikitina MA, Dorofeeva YB, Saltykova IV, Tyakht AV, Kostryukova ES, Sazonov AE. [Correlation Between Emotional-Affective Disorders and Gut Microbiota Composition in Patients with Parkinson's Disease]. Vestn Ross Akad Med Nauk. 2016;71(6):427-35. doi: 10.15690/vramn734. Russian.
- Background: PubMed 30114473Spielman LJ, Gibson DL, Klegeris A. Unhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases. Neurochem Int. 2018 Nov;120:149-163. doi: 10.1016/j.neuint.2018.08.005. Epub 2018 Aug 14.
- Background: PubMed 30658292Roy Sarkar S, Banerjee S. Gut microbiota in neurodegenerative disorders. J Neuroimmunol. 2019 Mar 15;328:98-104. doi: 10.1016/j.jneuroim.2019.01.004. Epub 2019 Jan 9.
- Background: PubMed 29782468Mazzini L, Mogna L, De Marchi F, Amoruso A, Pane M, Aloisio I, Cionci NB, Gaggia F, Lucenti A, Bersano E, Cantello R, Di Gioia D, Mogna G. Potential Role of Gut Microbiota in ALS Pathogenesis and Possible Novel Therapeutic Strategies. J Clin Gastroenterol. 2018 Nov/Dec;52 Suppl 1, Proceedings from the 9th Probiotics, Prebiotics and New Foods, Nutraceuticals and Botanicals for Nutrition & Human and Microbiota Health Meeting, held in Rome, Italy from September 10 to 12, 2017:S68-S70. doi: 10.1097/MCG.0000000000001042.
- Background: PubMed 29925252Wright ML, Fournier C, Houser MC, Tansey M, Glass J, Hertzberg VS. Potential Role of the Gut Microbiome in ALS: A Systematic Review. Biol Res Nurs. 2018 Oct;20(5):513-521. doi: 10.1177/1099800418784202. Epub 2018 Jun 20.
- Background: PubMed 31870202Erber AC, Cetin H, Berry D, Schernhammer ES. The role of gut microbiota, butyrate and proton pump inhibitors in amyotrophic lateral sclerosis: a systematic review. Int J Neurosci. 2020 Jul;130(7):727-735. doi: 10.1080/00207454.2019.1702549. Epub 2019 Dec 23.
- Individual participant dataSharing planned: Yes. Variables related to inflammation and oxidation: * Quantitative measurement of plasma IL-6 and TNF-alpha. * Quantitative measurement of plasma PCR. * Quantitative measurement of plasma haptoglobin. * Quantitative measurement of TEAC (oxidation). * Quantitative measurement of plasma 8-oxoG. * Quantitative measurement of plasma MDA. Variables for cognitive and behavioural assessment: * Edinburgh Cognitive and Behavioral ALS Screen * Frontal Assessment Battery (FAB)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
José Enrique De la Rubia Ortí, Ph principal investigator
Catholic University of Valencia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Liposomed polyphenols resveratrol and curcumin, Isocaloric Diet and G04CB02 in people with Amyotrophic Lateral Sclerosis, run by Fundación Universidad Católica de Valencia San Vicente Mártir at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale associated with ALS (time frame: Time 0). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04654689, which also lists 54 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2026.