Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects

Dyslipidemia Clinical Trial

— EBBINGHAUS  

Official title:

A Double-Blind, Placebo Controlled, Multicenter Study to Assess the Effect of Evolocumab on Cognitive Function in Patients With Clinically Evident Cardiovascular Disease and Receiving Statin Background Lipid Lowering Therapy: A Study for Subjects Enrolled in the FOURIER (Study 20110118) Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02207634
• Other study ID #: 20130385
• Secondary ID: 2014-001976-75
• Status: Completed
• Phase: Phase 3
• First received: July 31, 2014
• Last updated: December 15, 2017
• Start date: September 10, 2014
• Est. completion date: November 11, 2016

Study information

• Verified date: December 2017
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluated change over time in neurocognitive testing in patients receiving statin therapy in combination with evolocumab (AMG 145), compared with patients receiving statin therapy in combination with placebo.

Description:

Participants who were enrolled in study 20110118 (FOURIER; NCT01764633) at select sites in select countries (selected based on study start-up timelines) were invited to participate in this cognitive function study, 20130385. There was no separate randomization for Study 20130385; data were analyzed according to Study 20110118 randomized treatment arm.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1974
• Est. completion date: November 11, 2016
• Est. primary completion date: November 11, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 85 Years

Eligibility

Inclusion Criteria:

• Randomized into Study 20110118 (FOURIER; NCT01764633)

Exclusion Criteria:

• Current or known past diagnosis of dementia or mild cognitive impairment (MCI)

Related Conditions & MeSH terms

• Dyslipidemia
• Dyslipidemias

Intervention

Biological:
• Evolocumab
Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.

Drug:
• Placebo
Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.
• Background Statin Therapy
Participants were required to be on a stable, high- to moderate-intensity statin background therapy consisting of an effective statin dose, ie, at least atorvastatin 20 mg daily or equivalent, and where locally approved, highly effective statin therapy (defined as at least atorvastatin 40 mg daily or equivalent) was recommended.

Locations

Country	Name	City	State
Australia	Research Site	Adelaide	South Australia
Australia	Research Site	Ashford	South Australia
Australia	Research Site	Auchenflower	Queensland
Australia	Research Site	Box Hill	Victoria
Australia	Research Site	Epping	Victoria
Australia	Research Site	Fullarton	South Australia
Australia	Research Site	Geelong	Victoria
Australia	Research Site	Hobart	Tasmania
Australia	Research Site	Woden	Australian Capital Territory
Belgium	Research Site	Aalst
Belgium	Research Site	Bonheiden
Belgium	Research Site	Brussels
Belgium	Research Site	Brussels
Belgium	Research Site	Gozee
Belgium	Research Site	Ieper
Belgium	Research Site	La Louvière
Belgium	Research Site	Liege
Belgium	Research Site	Liège
Canada	Research Site	Chicoutimi	Quebec
Canada	Research Site	Gatineau	Quebec
Canada	Research Site	London	Ontario
Canada	Research Site	Newmarket	Ontario
Canada	Research Site	Newmarket	Ontario
Canada	Research Site	Peterborough	Ontario
Canada	Research Site	Pointe-Claire	Quebec
Canada	Research Site	Quebec
Canada	Research Site	Sarnia	Ontario
Canada	Research Site	St Jean sur Richelieu	Quebec
Canada	Research Site	St-Jérôme	Quebec
Canada	Research Site	St. Johns	Newfoundland and Labrador
Czechia	Research Site	Beroun
Czechia	Research Site	Bilovec
Czechia	Research Site	Brandys nad Labem
Czechia	Research Site	Brno
Czechia	Research Site	Brno
Czechia	Research Site	Brno
Czechia	Research Site	Chomutov
Czechia	Research Site	Havlickuv Brod
Czechia	Research Site	Hodonin
Czechia	Research Site	Klatovy IV
Czechia	Research Site	Liberec
Czechia	Research Site	Litomysl
Czechia	Research Site	Mohelnice
Czechia	Research Site	Olomouc
Czechia	Research Site	Ostrava - Vitkovice
Czechia	Research Site	Pardubice
Czechia	Research Site	Praha 10
Czechia	Research Site	Praha 2
Czechia	Research Site	Praha 3
Czechia	Research Site	Praha 4
Czechia	Research Site	Praha 5 - Smichov
Czechia	Research Site	Prerov
Czechia	Research Site	Uherske Hradiste
Denmark	Research Site	Aalborg
Denmark	Research Site	Ballerup
Denmark	Research Site	Esbjerg
Denmark	Research Site	Hvidovre
Denmark	Research Site	København S
Denmark	Research Site	Køge
Denmark	Research Site	Vejle
Estonia	Research Site	Paide
Estonia	Research Site	Tallinn
Estonia	Research Site	Tallinn
Estonia	Research Site	Tallinn
Finland	Research Site	Helsinki
Finland	Research Site	Helsinki
Finland	Research Site	Jyväskylä
Finland	Research Site	Kuopio
Finland	Research Site	Oulu
Finland	Research Site	OYS
Finland	Research Site	Tampere
Finland	Research Site	Turku
France	Research Site	Besançon Cedex
France	Research Site	Le Coudray
France	Research Site	Montepellier Cedex
France	Research Site	Nantes Cedex 1
France	Research Site	Paris
France	Research Site	Pessac Cedex
France	Research Site	Toulouse Cedex 9
Germany	Research Site	Bad Krozingen
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Bochum
Germany	Research Site	Dresden
Germany	Research Site	Frankfurt am Main
Germany	Research Site	Hamburg
Germany	Research Site	Hannover
Germany	Research Site	Köln
Germany	Research Site	Leipzig
Germany	Research Site	Stuttgart
Germany	Research Site	Witten
Germany	Research Site	Wuppertal
Greece	Research Site	Alexandroupoli
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Ioannina
Greece	Research Site	Larissa
Greece	Research Site	Piraeus
Hong Kong	Research Site	Hong Kong
Hungary	Research Site	Bekescsaba
Hungary	Research Site	Berettyoujfalu
Hungary	Research Site	Budapest
Hungary	Research Site	Nyiregyhaza
Hungary	Research Site	Pecs
Hungary	Research Site	Szeged
Hungary	Research Site	Szekszard
Hungary	Research Site	Szikszo
Hungary	Research Site	Zalaegerszeg
Italy	Research Site	Pavia
Japan	Research Site	Chikushi-gun	Fukuoka
Japan	Research Site	Chuo-ku	Tokyo
Japan	Research Site	Fukuoka-shi	Fukuoka
Japan	Research Site	Fukuoka-shi	Fukuoka
Japan	Research Site	Himeji-shi	Hyogo
Japan	Research Site	Ichinomiya-shi	Aichi
Japan	Research Site	Itoshima-shi	Fukuoka
Japan	Research Site	Kasugai-shi	Aichi
Japan	Research Site	Kawaguchi-shi	Saitama
Japan	Research Site	Komatsushima-shi	Tokushima
Japan	Research Site	Kyoto-shi	Kyoto
Japan	Research Site	Matsudo-shi	Chiba
Japan	Research Site	Nagoya-shi	Aichi
Japan	Research Site	Nagoya-shi	Aichi
Japan	Research Site	Nagoya-shi	Aichi
Japan	Research Site	Okinawa-shi	Okinawa
Japan	Research Site	Osaka-shi	Osaka
Japan	Research Site	Osaka-shi	Osaka
Japan	Research Site	Saga-shi	Saga
Japan	Research Site	Saga-shi	Saga
Japan	Research Site	Saijo-shi	Ehime
Japan	Research Site	Sapporo-shi	Hokkaido
Japan	Research Site	Shimajiri-gun	Okinawa
Japan	Research Site	Toride-shi	Ibaraki
Japan	Research Site	Toyohashi-shi	Aichi
Japan	Research Site	Tsukuba-city	Ibaraki
Japan	Research Site	Urasoe-shi	Okinawa
Latvia	Research Site	Daugavpils
Latvia	Research Site	Kuldiga
Latvia	Research Site	Liepaja
Latvia	Research Site	Ogre
Latvia	Research Site	Ogre
Latvia	Research Site	Riga
Latvia	Research Site	Riga
Lithuania	Research Site	Vilnius
Malaysia	Research Site	Kuala Lumpur	Wilayah Persekutuan
Malaysia	Research Site	Kuala Lumpur
Netherlands	Research Site	Arnhem
Netherlands	Research Site	Ede
Netherlands	Research Site	Eindhoven
Netherlands	Research Site	Hoorn
Netherlands	Research Site	Uden
New Zealand	Research Site	Christchurch
New Zealand	Research Site	Tauranga
Norway	Research Site	Ålesund
Norway	Research Site	Hamar
Norway	Research Site	Lierskogen
Norway	Research Site	Oslo
Norway	Research Site	Skedsmokorset
Norway	Research Site	Skien
Norway	Research Site	Stavanger
Poland	Research Site	Gdansk
Poland	Research Site	Gdynia
Poland	Research Site	Gdynia
Poland	Research Site	Katowice
Poland	Research Site	Katowice
Poland	Research Site	Katowice
Poland	Research Site	Kielce
Poland	Research Site	Krakow
Poland	Research Site	Krakow
Poland	Research Site	Lodz
Poland	Research Site	Lodz
Poland	Research Site	Lublin
Poland	Research Site	Olsztyn
Poland	Research Site	Poznan
Poland	Research Site	Pulawy
Poland	Research Site	Ruda Slaska
Poland	Research Site	Staszow
Poland	Research Site	Swidnik
Poland	Research Site	Tarnow
Poland	Research Site	Torun
Poland	Research Site	Warszawa
Poland	Research Site	Warszawa
Poland	Research Site	Warszawa
Poland	Research Site	Wloclawek
Poland	Research Site	Wroclaw
Poland	Research Site	Wroclaw
Poland	Research Site	Wroclaw
Poland	Research Site	Zamosc
Portugal	Research Site	Almada
Portugal	Research Site	Carnaxide
Portugal	Research Site	Coimbra
Portugal	Research Site	Covilha
Russian Federation	Research Site	Ekaterinburg
Russian Federation	Research Site	Ivanovo
Russian Federation	Research Site	Izhevsk
Russian Federation	Research Site	Kemerovo
Russian Federation	Research Site	Kemerovo
Russian Federation	Research Site	Kirov
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhniy Novgorod
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Omsk
Russian Federation	Research Site	Pushkin
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saratov
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	Tomsk
Slovakia	Research Site	Bardejov
Slovakia	Research Site	Brezno
Slovakia	Research Site	Kosice
Slovakia	Research Site	Lucenec
Slovakia	Research Site	Moldava nad Bodvou
Slovakia	Research Site	Nove Zamky
Slovakia	Research Site	Rimavska Sobota
Slovakia	Research Site	Roznava
Slovakia	Research Site	Snina
Slovakia	Research Site	Svidnik
Slovakia	Research Site	Trencin
Slovakia	Research Site	Trnava
South Africa	Research Site	Cape Town
South Africa	Research Site	Centurion	Gauteng
South Africa	Research Site	Johannesburg	Gauteng
South Africa	Research Site	Johannesburg	Gauteng
South Africa	Research Site	Kempton Park
South Africa	Research Site	Paarl	Western Cape
South Africa	Research Site	Parow	Western Cape
South Africa	Research Site	Pretoria	Gauteng
South Africa	Research Site	Pretoria west	Gauteng
South Africa	Research Site	Somerset West	Western Cape
South Africa	Research Site	Worcester	Western Cape
Spain	Research Site	Galdakao	País Vasco
Spain	Research Site	L'Hospitalet de Llobregat	Cataluña
Spain	Research Site	Madrid
Spain	Research Site	Santiago de Compostela	Galicia
Spain	Research Site	Valencia	Comunidad Valenciana
Spain	Research Site	Vigo	Galicia
Spain	Research Site	Zaragoza	Aragón
Sweden	Research Site	Helsingborg
Sweden	Research Site	Linköping
Sweden	Research Site	Lund
Sweden	Research Site	Stockholm
Sweden	Research Site	Stockholm
Sweden	Research Site	Uddevalla
Sweden	Research Site	Västerås
Turkey	Research Site	Adana
Turkey	Research Site	Ankara
Turkey	Research Site	Gaziantep
Turkey	Research Site	Istanbul
Turkey	Research Site	Istanbul
Turkey	Research Site	Izmir
Turkey	Research Site	Kocaeli
United Kingdom	Research Site	Belfast
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Bournemouth
United Kingdom	Research Site	Cardiff
United Kingdom	Research Site	Chesterfield
United Kingdom	Research Site	Chippenham
United Kingdom	Research Site	Chorley
United Kingdom	Research Site	Doncaster
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	Hexham
United Kingdom	Research Site	Leicester
United Kingdom	Research Site	Liverpool
United Kingdom	Research Site	Liverpool
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Newport
United Kingdom	Research Site	Nuneaton
United Kingdom	Research Site	Reading
United Kingdom	Research Site	Sandbach
United Kingdom	Research Site	Sheffield
United Kingdom	Research Site	West Bromwich
United Kingdom	Research Site	Whitby
United Kingdom	Research Site	Worcester
United States	Research Site	Addison	Illinois
United States	Research Site	Alhambra	California
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Atlanta	Georgia
United States	Research Site	Augusta	Georgia
United States	Research Site	Aurora	Colorado
United States	Research Site	Austin	Texas
United States	Research Site	Banning	California
United States	Research Site	Baton Rouge	Louisiana
United States	Research Site	Belleville	Illinois
United States	Research Site	Bend	Oregon
United States	Research Site	Biddeford	Maine
United States	Research Site	Birmingham	Alabama
United States	Research Site	Boynton Beach	Florida
United States	Research Site	Bridgeport	Connecticut
United States	Research Site	Brooklyn	New York
United States	Research Site	Buffalo	New York
United States	Research Site	Burke	Virginia
United States	Research Site	Calabash	North Carolina
United States	Research Site	Camp Hill	Pennsylvania
United States	Research Site	Canton	Ohio
United States	Research Site	Chambersburg	Pennsylvania
United States	Research Site	Chicago	Illinois
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Coeur d'Alene	Idaho
United States	Research Site	Colorado Springs	Colorado
United States	Research Site	Columbus	Ohio
United States	Research Site	Columbus	Ohio
United States	Research Site	Cortlandt Manor	New York
United States	Research Site	Crystal River	Florida
United States	Research Site	Dallas	Texas
United States	Research Site	Dayton	Ohio
United States	Research Site	Daytona Beach	Florida
United States	Research Site	Deerfield Beach	Florida
United States	Research Site	Denver	Colorado
United States	Research Site	Falls Church	Virginia
United States	Research Site	Feasterville	Pennsylvania
United States	Research Site	Fleming Island	Florida
United States	Research Site	Fort Mill	South Carolina
United States	Research Site	Gainesville	Georgia
United States	Research Site	Glendale	Arizona
United States	Research Site	Grand Forks	North Dakota
United States	Research Site	Grandville	Michigan
United States	Research Site	Great Falls	Montana
United States	Research Site	Green Bay	Wisconsin
United States	Research Site	Hammond	Louisiana
United States	Research Site	Hammond	Indiana
United States	Research Site	Harbor City	California
United States	Research Site	Haverhill	Massachusetts
United States	Research Site	Hickory	North Carolina
United States	Research Site	Hickory	North Carolina
United States	Research Site	Hollywood	Florida
United States	Research Site	Hollywood	Florida
United States	Research Site	Hopewell	Virginia
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Huntsville	Alabama
United States	Research Site	Hutchinson	Kansas
United States	Research Site	Jackson	Tennessee
United States	Research Site	Jacksonville	Florida
United States	Research Site	Jefferson City	Missouri
United States	Research Site	Jerseyville	Illinois
United States	Research Site	Kalispell	Montana
United States	Research Site	Lafayette	Louisiana
United States	Research Site	Laguna Hills	California
United States	Research Site	Lansing	Michigan
United States	Research Site	Lexington	Kentucky
United States	Research Site	Long Beach	California
United States	Research Site	Long Beach	California
United States	Research Site	Metairie	Louisiana
United States	Research Site	Miami	Florida
United States	Research Site	Mobile	Alabama
United States	Research Site	Moncks Corner	South Carolina
United States	Research Site	Monroe	Louisiana
United States	Research Site	Mooresville	North Carolina
United States	Research Site	Mount Pleasant	South Carolina
United States	Research Site	Muskegon	Michigan
United States	Research Site	Nashville	Tennessee
United States	Research Site	New Hyde Park	New York
United States	Research Site	New Windsor	New York
United States	Research Site	Newton	Massachusetts
United States	Research Site	North Myrtle Beach	South Carolina
United States	Research Site	Oceanside	California
United States	Research Site	Owensboro	Kentucky
United States	Research Site	Oxnard	California
United States	Research Site	Palm Harbor	Florida
United States	Research Site	Palm Springs	California
United States	Research Site	Pawtucket	Rhode Island
United States	Research Site	Pembroke Pines	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Phoenix	Arizona
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Plano	Texas
United States	Research Site	Ponte Vedra	Florida
United States	Research Site	Portland	Oregon
United States	Research Site	Portland	Oregon
United States	Research Site	Pryor	Oklahoma
United States	Research Site	Raleigh	North Carolina
United States	Research Site	Rapid City	South Dakota
United States	Research Site	Richmond	Virginia
United States	Research Site	Richmond	Virginia
United States	Research Site	Rochester	New York
United States	Research Site	Roseville	California
United States	Research Site	Sacramento	California
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Saint Paul	Minnesota
United States	Research Site	Saint Petersburg	Florida
United States	Research Site	Salisbury	Maryland
United States	Research Site	San Pedro	California
United States	Research Site	Sarasota	Florida
United States	Research Site	Savannah	Georgia
United States	Research Site	Seattle	Washington
United States	Research Site	Slidell	Louisiana
United States	Research Site	Springfield	Ohio
United States	Research Site	Suffolk	Virginia
United States	Research Site	Suwanee	Georgia
United States	Research Site	Tabor City	North Carolina
United States	Research Site	Tampa	Florida
United States	Research Site	Tarzana	California
United States	Research Site	Thousand Oaks	California
United States	Research Site	Toledo	Ohio
United States	Research Site	Towson	Maryland
United States	Research Site	Troy	New York
United States	Research Site	Tullahoma	Tennessee
United States	Research Site	Voorhees	New Jersey
United States	Research Site	Waterloo	Iowa
United States	Research Site	West Jordan	Utah
United States	Research Site	West Palm Beach	Florida
United States	Research Site	West Seneca	New York
United States	Research Site	Westwood	New Jersey
United States	Research Site	Wichita Falls	Texas
United States	Research Site	Williamsville	New York
United States	Research Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  Denmark,  Estonia,  Finland,  France,  Germany,  Greece,  Hong Kong,  Hungary,  Italy,  Japan,  Latvia,  Lithuania,  Malaysia,  Netherlands,  New Zealand,  Norway,  Poland,  Portugal,  Russian Federation,  Slovakia,  South Africa,  Spain,  Sweden,  Turkey,  United Kingdom, 

References & Publications (2)

Giugliano RP, Mach F, Zavitz K, Kurtz C, Im K, Kanevsky E, Schneider J, Wang H, Keech A, Pedersen TR, Sabatine MS, Sever PS, Robinson JG, Honarpour N, Wasserman SM, Ott BR; EBBINGHAUS Investigators. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med. 2017 Aug 17;377(7):633-643. doi: 10.1056/NEJMoa1701131. — View Citation

Giugliano RP, Mach F, Zavitz K, Kurtz C, Schneider J, Wang H, Keech A, Pedersen TR, Sabatine MS, Sever PS, Honarpour N, Wasserman SM, Ott BR; EBBINGHAUS Investigators. Design and rationale of the EBBINGHAUS trial: A phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy-A cognitive study of patients enrolled in the FOURIER trial. Clin Cardiol. 2017 Feb;40(2):59-65. doi: 10.1002/clc.22678. Epub 2017 Feb 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change From Baseline in Spatial Working Memory Strategy Index of Executive Function (6-8 Boxes) Z Score	Assessments were performed with the Cambridge Neuropsychological Test Automated Battery (CANTAB), a language-independent battery of computerized tests that is used to assess cognitive function.; The Spatial Working Memory (SWM) test assesses the cognitive domain of executive function (high-level thinking and decision making). Patients search for colored tokens hidden inside boxes on the screen by touching them. The critical instruction is that once a token has been found inside a box, there will never be a token hidden inside that box again, so patients must not return to a box where a token has been found.; The SWM strategy index of executive function represented the number of times a subject began a search with a different box. The Z score represents the standardized measure of how far an individual subject deviates from the study cohort average at baseline. A higher Z score reflects better performance. The mean change from baseline averaged across all the visits is reported.	Assessments were conducted at Baseline and at weeks 24, 48, 96, 144 and end of study visit (median time on study was 19.4 months).
Secondary	Mean Change From Baseline in Spatial Working Memory (SWM) Between-errors Z Score	Assessments were performed with the CANTAB, a language-independent battery of computerized tests that is used to assess cognitive function. The Spatial Working Memory (SWM) between-errors test assesses the cognitive domain of working memory (holding material in mind while that material is being actively processed). Patients search for colored tokens hidden inside boxes on the screen by touching them. The critical instruction is that once a token has been found inside a box, there will never be a token hidden inside that box again, so patients must not return to a box where a token has been found.; The SWM between-errors score is the number of times that a patient revisited a box in which a token had previously been found. The Z score represents the standardized measure of how far an individual participant deviates from the study cohort average at baseline. A higher Z score reflects better performance. The mean change from baseline averaged across all the visits is reported.	Assessments were conducted at Baseline and at weeks 24, 48, 96, 144 and end of study visit (median time on study was 19.4 months).
Secondary	Mean Change From Baseline in Paired Associated Learning (PAL) Total Errors Adjusted Z Score	The CANTAB PAL test assesses visuospatial episodic memory (storing/retrieving information by associating an event with a time and place). Boxes on the screen opened up one at a time to reveal a number of patterns. Participants were asked to remember the location of each pattern. After all the boxes had been opened, each pattern was then shown in the center of the screen in a randomized order, and the patient should touch the box where they think each pattern was hidden. The PAL total errors adjusted comprised the number of errors committed by a patient plus an adjustment for the estimated number of errors the patient would have made on any stages that were not reached.; Z score represents the standardized measure of how far an individual patient deviates from the study cohort average at baseline. A higher Z score indicated better performance. The mean change from baseline averaged across all the visits is reported.	Assessments were conducted at Baseline and at weeks 24, 48, 96, 144 and end of study visit (median time on study was 19.4 months).
Secondary	Mean Change From Baseline in Reaction Time (RTI) Median 5-choice Reaction Time Z Score	Assessments were performed with the CANTAB, a language-independent battery of computerized tests that is used to assess cognitive function. The Reaction Time (RTI) test assessed the cognitive domain of psychomotor speed (detecting and responding to a stimulus). Participants held down a button until a spot appeared in 1 of 5 circles on the screen. As soon as possible after the spot flashed up, the patient lifted their finger from the button and touched the circle in which the spot appeared. The RTI median 5-choice reaction time was the median duration between the onset of the stimulus and the release of the button. Z score represents the standardized measure of how far an individual participant deviates from the study cohort average at baseline. A higher Z score reflects better performance. The mean change from baseline averaged across all the visits is reported.	Assessments were conducted at Baseline and at weeks 24, 48, 96, 144 and end of study visit (median time on study was 19.4 months).

External Links

•   AmgenTrials clinical trials website