E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Normal pressure hydrocephalus |
Normaltryckshydrocefalus |
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E.1.1.1 | Medical condition in easily understood language |
Hydrocephalus |
Vattenskalle |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020510 |
E.1.2 | Term | Hydrocephalus acquired |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To examine the effect of acetazolamide on gait in patients with normal pressure hydrocephalus. |
Att undersöka om behandling med ACZ till patienter med iNPH förbättrar gångförmågan. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to study: • The changes in subjective symptoms and change in life quality over time in patients with normal pressure hydrocephalus treated with acetazolamide. • Changes in the MRI parameters of patients with normal pressure hydrocephalus treated with acetazolamide, with focus on: periventricular white matter hyperintensities, cerebral blood flow, and brain morphology. • The safety profile of and side effects in patients with normal pressure hydrocephalus treated with acetazolamide. • Changes in the concentration of biomarkers in the blood after treatment with acetazolamide. • Changes in the concentration of biomarkers in the cerebrospinal fluid after treatment with acetazolamide.
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De viktigaste sekundära frågeställningarna: • Påverkas symtomutveckling och livskvalitet över tid hos patienter med iNPH som behandlas med acetazolamid? • Förändras den radiologiska bilden hos patienter med iNPH som behandlas med acetazolamid med fokus på: PVH, cerebralt blodflöde, och hjärnans morfologi? • Vad är säkerhetsprofilen och vilka biverkningar inträffar hos patienter med iNPH som behandlas med acetazolamid? • Förändras biomarkörer i blod efter behandling med acetazolamid? • Förändras biomarkörer i CSF efter behandling med acetazolamid?
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis of idiopathic normal pressure hydrocephalus according to international guidelines 2. Age ≥50 years and ≤ 82 years 3. Cognitive function with Mini-Mental State Examination > 20 points or cognitive domain of the iNPH scale ≥30 points 4. MRI image for iNPH defined as callosal angle <95 degrees and dilated lateral ventricles or image as in disproportionately subarachnoid space hydrocephalus (DESH) 5. Signed informed consent form
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1. Sannolik idiopatisk NPH enligt internationella guidelines 2. Ålder ≥50 år och ≤ 82 år 3. Kognitiv förmåga med MMSE >20 poäng eller kognitiva domänen av iNPH skalan ≥30 poäng 4. Radiologisk typisk bild för iNPH definierat som callosal angle <95 grader och vidgade sidoventriklar eller bild som vid disproportionately subarachnoid space hydrocephalus (DESH) 5. Signerat samtycke
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E.4 | Principal exclusion criteria |
1. Exclusion criteria for MRI examination 2. Participation in another medical trial 3. Other disease likely to impact the symptoms of the patient 4. Wheelchair bound or in need of support when walking 5. Reduced kidney function with creatinine GFR < 50 6. Reduced liver function: Prothrombin complex > 1.2 or increased alanine transaminase concentrations in plasma 1.5 times above the upper reference value (women > 1.125 mkat/L; men > 1.65 mkat/L). 7. Known heart failure 8. Low concentrations of electrolytes in blood plasma, or other illness or treatment that may cause significant lowering of electrolyte concentrations according to the investigator 9. Angle-closure glaucoma 10. Allergy to acetazolamide, sulfonamides, or sulfonamide derivatives 11. Treatment with phenytoin, valproate, carbamazepine, lithium, thiazide-diuretics > 25mg/day, acetylsalicylic acid > 100 mg/day, daily use of NSAID or furosemide > 20 mg/day 12. Inability to swallow capsules of the same size as the investigational medicinal products (will be tested using empty capsules when the patient is asked to participate in the study) 13. Average walking time for the three walking tests <10.5 seconds for men and <11.5 seconds for women 14. Average walking time for the three walking tests > 50 seconds 15. Inability to comply with the study treatment independently, and a concurrent lack of individuals to help the patient comply with the treatment during the study period 16. Females who are not infertile or females of childbearing potential who do not use highly effective birth control. For females of childbearing potential a negative pregnancy test will be documented before inclusion |
1. Exklusionskriterier för att genomgå MRT 2. Inkluderad i annan klinisk läkemedelsstudie 3. Annan sjukdom som tros ha stor betydelse för forskningspersonens symptom 4. Helt rullstolsburen eller behov av gånghjälpmedel för förflyttningar 5. Nedsatt njurfunktion med kreatininberäknat GFR <50 6. Nedsatt leverfunktion: Protrombinkomplex (PK) > 1,2 eller förhöjt alaninaminotransferas i plasma 1,5 gånger över övre referensvärde (Kvinnor > 1,125 mkat/L; Män >1,65 mkat/L). 7. Känd hjärtsvikt 8. Sänkta elektrolytvärden i blodplasma, annan sjukdom eller behandling som riskerar att orsaka betydande sänkning av elektrolytvärden enligt ansvarig studieläkare 9. Trångvinkelglaukom 10. Allergi mot acetazolamid, sulfonamider eller sulfonamidderivat 11. Behandling med fenytoin, valproat, karbamazepin, litium, thiazid-diuretika > 25 mg/dag, acetylsalicylsyra > 100 mg/dag, daglig användning av NSAID eller furosemid > 20 mg/dag 12. Oförmåga att svälja kapslar med samma storlek som studieläkemedlet (testas med tomma kapslar när forskningsperson tillfrågas om deltagande) 13. Medelgångtid för de tre gångtesterna <10,5 sekunder för män och <11,5 sekunder för kvinnor 14. Medelgångtid för de tre gångtesterna >50 sekunder 15. Oförmåga att hantera läkemedel självständigt och samtidigt avsaknad av person som kan hjälpa forskningspersonen med läkemedel under studietiden 16. Kvinna som inte är infertil eller fertil kvinna utan högeffektiv antikonception. Fertil kvinna kommer att testas med graviditetstest innan inklusion är möjlig.
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E.5 End points |
E.5.1 | Primary end point(s) |
The relative change in gait between walking trials is the primary outcome measure. Walking is examined as the sum of time and steps required to walk a distance of 10 meters, timed up-and-go (TUG), and walking backwards for 3 meters. |
Gångförmåga undersökt som summan av tid och steg för 10 m gång, timed up-and-go (TUG) samt 3 m baklängesgång. Relativ förändring i gångförmåga mellan mättillfällen är primärt utfallsmått. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Relative change in gait between visit 1 and 3 is considered the primary endpoint. |
Relativ förändring i gångförmåga mellan besök 1 och 3 primärt utfallsmått. |
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E.5.2 | Secondary end point(s) |
• Quality of life assessed by o The EQ-5D-5L self-completion questionnaire o Questionnaires 1-2 that estimate the patient’s own experience of symptoms and side effects, respectively. • The volume of periventricular white matter calculated by volumetric analysis of brain MRI • Cerebral blood flow analysed by arterial spin labeling MRI • Changes in the fluid composition of the brain analysed by synthetic MRI • The total symptomatic change in motor skills, cognition, and continence, assessed using the Swedish iNPH scale • Blood and cerebrospinal fluid biomarkers (neurofilament light chain protein [NFL], amyloid-beta-42, Tau, and glial fibrillary acidic protein [GFAp])
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• Tester av livskvalitet genom att patienter ifyller o EQ-5D-5L frågeformulär o Frågeformulär 1-2 som skattar forskningspersonens egen upplevelse av symptom respektive biverkningar • Volymen av PVH beräknat med volumetri på MRT av hjärna. • Cerebralt blodflöde undersökt med arterial spin labeling MRT. • Förändring av hjärnans vätskeinnehåll undersökt med Syntetisk MR. • Total symtombild av motorik, kognition och kontinens undersökt med den Svenska iNPH-skalan • Biomarkörer i blod och CSF (neurofilament light chain protein (NFL), amyloid-beta-42, Tau och glial fibrillary acidic protein (GFAp).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
MRI performed during the initial visit, and 3 months after start of treatment. Questionnaires are completed: during the initial visit, and during the telephone follow-up at 2-3 weeks, 6-7 weeks, and 3 months after start of treatment, and prior to the shunt surgery, and 3 months after surgery Cognitive tests are performed: at the initial visit, 3 months after start of treatment, prior to shunt surgery, and 3 months after surgery Blood samples for analysis of electrolytes, creatinine, and transaminases collected at: the initial visit, prior to telephone follow-up at 2-3 weeks and 6-7 weeks after start of treatment, 3 months after start of treatment, prior to the shunt surgery, and 3 months after surgery.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |