- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04987671
Pharmacokinetic and Pharmacodynamic Study of AMX0035 in Patients With ALS
A Pharmacokinetic and Pharmacodynamic Study of AMX0035 in Patients With ALS
Study Overview
Detailed Description
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Florida
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Gainesville, Florida, United States, 32608
- Norman Fixel Institute for Neurological Diseases
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Male or female, >=18years of age;
- Diagnosis of sporadic ALS (definite, probable, laboratory probable, possible) made by physician experienced with management of ALS as defined by the World Federation of Neurology revised El Escorial criteria;
- If taking riluzole, must be on a stable dose for >30 days prior to Day 1 and anticipated to remain at that dose until the final study visit.
- If taking edaravone, must be on a stable regimen for > 30 days prior to Day 1 and infusion(s) can be scheduled to be performed at no less than 48 hours prior or after the planned pharmacokinetic and pharmacodynamic (PK/PD) sampling.
- Capable of providing informed consent and following trial procedures;
- Geographically accessible to the site;
- Able to undergo the study procedures (including planned sampling on 3 occasions) and to adhere to the visit schedule, as determined by Investigator;
Women of child bearing potential (e.g. not post-menopausal for at least one year or surgically sterile) must agree to use adequate birth control for the duration of the study and 3 months after last dose of study drug;
a. Women must not be planning to become pregnant for the duration of the study and 3 months after last dose of study drug
Men must agree to practice contraception for the duration of the study and for at least 3 months after last dose of study drug;
- Men must not plan to father a child or provide sperm for donation for the duration of the study and 3 months after last dose of study drug
Acceptable birth control methods for use in this study are:
- Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants
- Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm)
- Intrauterine device (IUD)
- Abstinence (no heterosexual sex)
- Unique partner who is surgically sterile (men) or not of child bearing potential (female)
Exclusion Criteria:
- Familial ALS
- Forced vital capacity < 50% (or alternatively SVC) or presence of tracheostomy or under PAV (PAV is defined as more than 22 hours daily of non-invasive mechanical ventilation for more than 7 days);
- Planned elective surgery (such as feeding tube or edaravone access port placement) during the duration of the study;
- History of known allergy to PB or bile salts;
- Abnormal liver function defined as aspartate aminotransferase and/or alanine aminotransferase (AST and/or ALT) > 3 times the upper limit of the normal;
- Renal insufficiency as defined by eGFR < 60 mL/min/1.73m2;
- Ongoing Anemia with Hg concentration < 10.0 g/dL
- Pregnant women or women currently breastfeeding;
- Current biliary disease which may lead to biliary obstruction or impedes biliary flow including active cholecystitis, primary biliary cirrhosis, sclerosing cholangitis, gallbladder cancer, gallbladder polyps, gangrene of the gallbladder, abscess of the gallbladder;
- History of Class III/IV heart failure (per New York Heart Association - NYHA);
- Patient under severe salt restriction where the added salt intake due to treatment would put the patient at risk, in the Site Investigator clinical judgement;
- Presence of unstable psychiatric disease, cognitive impairment, dementia or substance abuse that would impair ability of the subject to provide informed consent, according to Site Investigator judgment;
- Presence of an active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period.
- Clinically significant unstable medical condition (other than ALS) that would pose a risk to the subject if they were to participate in the study, according to Site Investigator judgment.
- Clinically significant, as determined by the Investigator, 12-lead ECG abnormalities at screening.
- Treatment, current or within 90 days from start of study treatment, with any cell therapies or gene therapies;
- Treatment, current or within 90 days from start of study treatment, with experimental medication (for ALS or other indications)
- Current or anticipated need for a Diaphragm Pacing System (DPS);
- Anything that, in the opinion of the Site Investigator preclude the subject's full compliance with or completion of the study;
Exposure to any disallowed medications listed below:
HDAC Inhibitors including:
- Valproate
- Vorinostat (Zolinza)
- Romidepsin
- Chidamide
- Panobinostat
- Lithium
- Butyrate
- Suramin
- Probenecid
Bile Acid Sequestrants including:
- Cholestyramine and Cholestyramine Light
- Questran and Questran Light
- Welchol
- Colestid and Colestid Flavored
- Prevalite
Product that may interact with sterol absorption or excretion
- Ezetimibe
Note on Antacids within Two Hours of AMX0035 Administration: Antacids containing aluminum hydroxide or smectite (aluminum oxide) may not be taken within two hours of administration of MX0035 as they inhibit absorption of taurursodiol. These include:
- Alamag
- Alumina and Magnesia
- Antacid, Antacid M and Antacid Suspension
- Gen-Alox
- Kudrox
- M.A.H.
- Maalox HRF and Maalox TC
- Magnalox
- Maldroxal
- Mylanta and Mylanta Ultimate
- Ri-Mox
- Rulox
- Clinically significant, in the opinion of the Investigator, infection or inflammation at time of screening or admission.
- Acute gastrointestinal symptoms (eg, nausea, vomiting, diarrhea) at time of screening or admission or a or clinical diagnosis of irritable bowel syndrome (IBS) per ROME criteria (Appendix 7).
- Any current or previous illicit use of Class A drugs such as opiates, cocaine, ecstasy, LSD, and amphetamines (Class B).
- An alcoholic intake greater than 14 units per week or unwillingness to stop alcohol consumption for the duration of the study. Note: 1 unit = 8 g ethanol (250 mL of beer or approximately 10 oz, 1 glass wine [100 mL or approximately 3 oz], 1 measure spirits [30 mL or approximately 1 oz]).
- Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of investigational product.
- History of plasma/blood donation in the last 2 months.
- Any condition, which compromises ability to give informed consent or to communicate with the Investigator as required for the completion of this study.
- Unwilling to conform to all lifestyle considerations and restrictions mandated by the protocol.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Treatment with AMX0035
Two sequential study period.
In Period 1, subject receive AMX0035 daily for approximately 14 days.
In Period 2, subjects receive AMX0035 twice a day, morning and evening, for up to 25 days.
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Fixed dose combination of Sodium Phenylbutyrate and taurursodiol.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Blood concentration of PB and taurursodiol
Time Frame: Between Day 1 and Day 40
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Maximum plasma concentration - Cmax of PB and taurursodiol
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Between Day 1 and Day 40
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Systemic exposure to PB and taurursodiol
Time Frame: Between Day 1 and Day 40
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Area under the plasma concentration versus time curve - AUC of PB and taurursodiol
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Between Day 1 and Day 40
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Effect of demographic characteristics on blood concentration of PB and taurursodiol
Time Frame: Between Day 1 and Day 40
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Maximum plasma concentration - Cmax of PB and taurursodiolin relation to gender, body weight and age.
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Between Day 1 and Day 40
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Effect of demographic characteristics on systemic exposure of PB and taurursodiol
Time Frame: Between Day 1 and Day 40
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Area under the plasma concentration versus time curve - AUC of PB and taurursodiol relation to gender, body weight and age.
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Between Day 1 and Day 40
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Effect of a fixed dose combination of sodium phenyl butyrate (PB) and taurursodiol on pharmacodynamic activity
Time Frame: Between Day 1 and Day 40
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Histone 3 and histone 4 acetylation levels in peripehral blood mononuclear cells (PBMC)
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Between Day 1 and Day 40
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Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- Cuadrado-Tejedor M, Ricobaraza AL, Torrijo R, Franco R, Garcia-Osta A. Phenylbutyrate is a multifaceted drug that exerts neuroprotective effects and reverses the Alzheimer s disease-like phenotype of a commonly used mouse model. Curr Pharm Des. 2013;19(28):5076-84. doi: 10.2174/1381612811319280006.
- Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown RH Jr, Zhang H, Schoenfeld DA, Shefner J, Matson S, Matson WR, Ferrante RJ; Northeast ALS and National VA ALS Research Consortiums. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler. 2009 Apr;10(2):99-106. doi: 10.1080/17482960802320487.
- Lo AC, Callaerts-Vegh Z, Nunes AF, Rodrigues CM, D'Hooge R. Tauroursodeoxycholic acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice. Neurobiol Dis. 2013 Feb;50:21-9. doi: 10.1016/j.nbd.2012.09.003. Epub 2012 Sep 10.
- Ricobaraza A, Cuadrado-Tejedor M, Marco S, Perez-Otano I, Garcia-Osta A. Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus. 2012 May;22(5):1040-50. doi: 10.1002/hipo.20883. Epub 2010 Nov 10.
- Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A, Frechilla D, Del Rio J, Garcia-Osta A. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model. Neuropsychopharmacology. 2009 Jun;34(7):1721-32. doi: 10.1038/npp.2008.229. Epub 2009 Jan 14.
- Rodrigues CM, Sola S, Sharpe JC, Moura JJ, Steer CJ. Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry. 2003 Mar 18;42(10):3070-80. doi: 10.1021/bi026979d.
- Wiley JC, Pettan-Brewer C, Ladiges WC. Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice. Aging Cell. 2011 Jun;10(3):418-28. doi: 10.1111/j.1474-9726.2011.00680.x. Epub 2011 Mar 22.
- Zhou W, Bercury K, Cummiskey J, Luong N, Lebin J, Freed CR. Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem. 2011 Apr 29;286(17):14941-51. doi: 10.1074/jbc.M110.211029. Epub 2011 Mar 3.
- Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, D'Hooge R, Rodrigues CM. TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-beta deposition in APP/PS1 mice. Mol Neurobiol. 2012 Jun;45(3):440-54. doi: 10.1007/s12035-012-8256-y. Epub 2012 Mar 23.
- Dionisio PA, Amaral JD, Ribeiro MF, Lo AC, D'Hooge R, Rodrigues CM. Amyloid-beta pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset. Neurobiol Aging. 2015 Jan;36(1):228-40. doi: 10.1016/j.neurobiolaging.2014.08.034. Epub 2014 Sep 28.
- Wright JM, Zeitlin PL, Cebotaru L, Guggino SE, Guggino WB. Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11. doi: 10.1152/physiolgenomics.00160.2003.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Other Study ID Numbers
- A35-005
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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