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    EudraCT Number:2011-004798-99
    Sponsor's Protocol Code Number:0903010259
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-12-27
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2011-004798-99
    A.3Full title of the trial
    Safety and Efficacy of SOD1 Inhibition By Pyrimethamine in Familial (ALS)
    Verträglichkeit und Wirksamkeit der SOD1 (Superoxiddismutase 1) Inhibition durch Pyrimethamin bei Patienten mit familiärer amyotropher Lateralsklerose (ALS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and Efficacy of SOD1 Inhibition By Pyrimethamine in Familial (ALS)
    Verträglichkeit und Wirksamkeit der SOD1 (Superoxiddismutase 1) Inhibition durch Pyrimethamin bei Patienten mit familiärer amyotropher Lateralsklerose (ALS)
    A.3.2Name or abbreviated title of the trial where available
    Pyrimethamine In Familial ALS
    Pyrimethamin bei familiärer ALS
    A.4.1Sponsor's protocol code number0903010259
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorWeill Medical College of Cornell University
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMuscular Dystrophy Association
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinik für Neurologie der Universität Ulm
    B.5.2Functional name of contact pointAlbert C. Ludolph
    B.5.3 Address:
    B.5.3.1Street AddressOberer Eselsberg 45
    B.5.3.2Town/ cityUlm
    B.5.3.3Post code89081
    B.5.4Telephone number004907311771201
    B.5.5Fax number004907311771202
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Daraprim
    D. of the Marketing Authorisation holderGlaxoSmithKline
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 58-14-0
    D.3.9.4EV Substance CodeSUB10169MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Familial amyotrophic lateral sclerosis (FALS)
    Familiäre Amyotrophe Lateralsklerose (FALS)
    E.1.1.1Medical condition in easily understood language
    Familial amyotrophic lateral sclerosis (FALS)
    Familiäre Amyotrophe Lateralsklerose (FALS)
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10036704
    E.1.2Term Primary lateral sclerosis
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the ability of pyrimethamine to reduce SOD1 protein by 15% in the cerebrospinal fluid in patients with FALS at doses of 75 mg or less.
    Reduktion des SOD1 Proteins um 15% durch Pyrimethamin im Liquor von Patienten mit FALS
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of pyrimethamine in patients with FALS.
    Verträglichkeit (AEs) von Pyrimethamin Bei Patienten mit FALS
    Bestimmung, ob Pyrimethamin einen für SOD1 Mutationen spezifischen Effekt hat
    oder ob auch andere Mutationen bei Patienten mit FALS einen Effekt davon haben
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. ALS diagnosed as probable, laboratory supported probable or definite according to the World Federation of Neurology El Escorial criteria
    2. Age 18 or older
    3. Capable of providing informed consent and complying with trial procedures
    4. SOD1 mutation confirmation by study team
    5. Not taking Riluzole (Rilutek) or on a stable dose for 30 days
    6. Not taking Coenzyme QR10R or on a stable dose and brand for 30 days
    1. Patienten mit wahrscheinlicher, Laborgestützter wahrscheinlicher oder definitiver ALS gemäß den El Escorial Kriterien der World Federation of Neurology (Brooks et al. 2000)
    2. Alter 18 Jahre oder älter
    3. Fähigkeit zur Einwilligung in die Studienbeteiligung und zur Durchführung der verschiedenen Studienprocedere
    4. Bestätigte SOD1 Mutation
    5. Keine Einnahme von Riluzol oder Einnahme von Riluzol einer fixen Dosis seit 30 Tagen
    6. Keine Einnahme von Coenzym Q10 oder Einnahme einer fixen Dosis sowie des gleichen Präparats seit 30 Tagen
    E.4Principal exclusion criteria
    1. History or evidence of malabsorption syndromes
    2. Exposure to any experimental agent within 30 days of onset of this protocol
    3. Women who are pregnant or planning to become pregnant
    4. Women of childbearing potential not practicing contraception
    5. Women who are breastfeeding
    6. Enrollment in another research study within 30 days of or during this trial
    7. Alcoholism
    8. Patients taking phenytoin (Dilantin) or other therapy affecting folate levels
    9. Dementia (MMSE <22)
    10. Seizure disorder
    11. Folate deficiency
    12. Megaloblastic anemia
    13. Cardiovascular disorder/arrhythmia
    14. Impaired kidney function, defined as creatinine levels of 2.5 x ULN
    15. Impaired liver function, defined as AST or ALT of 3 X ULN
    16. Advanced ALS patients, defined as those with any of the following: forced vital capacity <60%
    (use of BIPAP is allowed); traecheostomy; or mechanical ventilation
    17. Use of any of the following medications: cytosine, arabinoside, methotrexate, daunorubicin,
    sulfonamides, zidovudine, lorazapam, coumadin, sulfamethoxazole, and trimethoprim
    18. Patients taking Lithium within 30 days of or during this trial
    19. Incapable of providing informed consent and complying with trial procedures
    1. Nachgewiesenes oder in der Anamnese vorhandenes Malabsorptionssyndrom
    2. Teilnahme an einer klinischen Studie innerhalb der letzten 30 Tage vor Studieneinschluss
    3. Schwangerschaft bzw. Patientinnen, die eine Schwangerschaft planen
    4. Patinnen im gebärfähigen Alter ohne ausreichende Kontrazeption
    5. Patientinnen während der Stillzeit
    6. Teilnahme an einer klinischen Studie innerhalb der letzten 30 Tage während dieser Studie
    7. Alkoholabhängigkeit
    8. Einnahme von Phenytoin oder anderen Substanzen, die den Folsäurespiegel beeinflussen
    9. Demenz (MMSE kleiner 22)
    10. Epilepsie
    11. Folsäuremangel
    12. Megaloblastenanämie
    13. Kardiovaskuläre Erkrankungen/Arrythmien
    14. Eingeschränkte Nierenfunktion, Kreatinin 2,5 x ULN
    15. Eingeschränkte Leberfunktion, AST oder ALT 3 x ULN
    16. Patienten mit fortgeschrittener ALS, bei denen eines der folgenden Kriterien erfüllt ist: FVC kleiner 60% (Anwendung von BIPAP ist erlaubt), Tracheostomie oder mechanische Beatmung
    17. Einnahme folgender Medikamente: Cytosin, Arabinoside, Methotrexat, Daunorubicin, Sulfonamide, Zidovudin, Lorazepam, Warfarin, Sulfamethoxazole, Trimethoprim
    18. Patienten, die Lithium innerhalb der letzten 30 Tage vor Einschluss oder während der Studie einnehmen
    19. Unfähigkeit zur Einwilligung in die Studienbeteiligung und zur Durchführung der verschiedenen Studienprocedere
    E.5 End points
    E.5.1Primary end point(s)
    reduction of SOD1 protein for 15 % in the cerebrospinal fluid in patients with FALS with pyrimethamin
    Reduktion des SOD1 Proteins um 15% durch Pyrimethamin im Liquor von Patienten mit FALS
    E.5.1.1Timepoint(s) of evaluation of this end point
    last visit (week 36)
    letzte Visite (36. Woche)
    E.5.2Secondary end point(s)
    Safety and tolerability of pyrimethan in patients with FALS due to measure safety and tolerability by adverse events, laboratory data,
    and ability to remain on assigned treatment.
    Verträglichkeit von Pyrimethamin bei Patienten mit FALS durch Erfassung von AEs, SAEs, Vitalparameter, Laborparameter und EKG
    Bestimmung, ob Pyrimethamin ein mutationsspezifischen Effekt bei SOD1 Mutationen aufweist oder ob es bei anderen Mutationen von Patienten mit FALS ebenfalls wirksam ist
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety and tolerability will be assessed every week, either during the study visit or by phone interview.
    Erfassung von Sicherheit und Verträglichkeit: wöchentlich (während einer Visite oder durch ein Telefoninterview)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E. trial type description
    Safety and Efficacy
    Sicherheit und Effektivität
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    letzer Patient letzte Visite
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months12
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 8
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1
    F.4.2.2In the whole clinical trial 40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-02-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-29
    P. End of Trial
    P.End of Trial StatusCompleted
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