Clinical Trials Register

Summary
EudraCT Number:	2018-000148-24
Sponsor's Protocol Code Number:	1
National Competent Authority:	Norway - NOMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-04-10
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Norway - NOMA

A.2

EudraCT number

2018-000148-24

A.3

Full title of the trial

Safety and efficacy of plasma transfusion from exercise-trained donors in patients with early Alzheimer’s disease: the ExPlas Study

Trent plasma som behandling for tidlig Alzheimers sykdom

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Safety and efficacy of plasma transfusion from exercise-trained donors in patients with early Alzheimer’s disease: the ExPlas Study

Trent plasma som behandling for tidlig Alzheimers sykdom

A.4.1

Sponsor's protocol code number

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Norwegian University of Science and Technology
B.1.3.4	Country	Norway
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Norwegian University of Science and Technology, NTNU
B.4.2	Country	Norway
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Norwegian University of Science and Technology, NTNU
B.5.2	Functional name of contact point	NTNU
B.5.3	Address:
B.5.3.1	Street Address	Post Box 8905
B.5.3.2	Town/ city	Trondheim
B.5.3.3	Post code	7491
B.5.3.4	Country	Norway
B.5.6	E-mail	ulrik.wisloff@ntnu.no

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Exercised Plasma
D.3.2	Product code	ExPlas
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Albumin
D.3.9.1	CAS number	70024-90-7
D.3.9.2	Current sponsor code	ExPlas
D.3.9.3	Other descriptive name	ALBUMIN
D.3.9.4	EV Substance Code	SUB20532
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	Yes
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Octaplasma
D.2.1.1.2	Name of the Marketing Authorisation holder	Octapharma
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Octaplasma
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	Yes
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solvent for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Early Alzheimer's disease

Alzheimers sykdom i tidlig fase

E.1.1.1

Medical condition in easily understood language

Early Alzheimer's disease

Alzheimers sykdom i tidlig fase

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The purpose of this study is to explore the safety of transfusion of plasma from exercise trained donors (ExPlas) compared to Octaplasma®, a commercially available virus inactivated plasma product pooled from approximately 1000 donors, and Sodium Chloride 0.9% (saline) in patients in the early symptomatic phase of AD and provide pilot data regarding efficacy. An additional aim is to provide advancements to the field by exploring therapeutical effects on AD of blood-borne factors.

Primary endpoint of ExPlas
Proportion of patients with adverse events after 1 year as a measure of safety and tolerability, and number of subjects who comply with the research protocol as a measure of feasibility.

Primærmål for studien er å teste sikkerhet og tolerabilitet av plasma transfusjoner fra trente donorer i pasienter med tidlig Alzheimers sykdom.

E.2.2

Secondary objectives of the trial

Secondary endpoints of ExPlas after 1, 2 and 5 years
 Change in performance in the CERAD (The Consortium to Establish a Registry for Alzheimer’s Disease) Ten word Test
 Change in the Mini-Mental State Examination Score
 Change in performance in Trail-Making test A and B
 Change in scores in other cognitive tests: the Clock Drawing Test, Controlled Oral Word Association
Test (COWAT)-FAS, Visual Object and Space Perception (VOSP) Silhouettes
 Change in Clinical Dementia Rating Scale Global score and Sum of Boxes, and The Lawton Instrumental Activities of Daily Living Scale (IADL)
 Change in performance in the 6-minutes walk-test
 Change in/Reduced hippocampal atrophy and preservation of functional connectivity assessed by resting state functional MRI
 Change in score of quality-of-Life SF-36 Questionnaire
 Change in biomarkers in blood and cerebrospinal fluid
 Change in cardiac dimensions, volumes and functional indices

Sekundærmål for studien er å teste gjennomførbarhet og effekten av plasma fra trente donorer på ulike parametere: kognitiv funksjon, kondisjon, vaskulær risikoprofil, vurdering av cerebral blodstrøm, strukturelle og funksjonelle MR mål, livskvalitet og biomarkører i blod og spinalvæske.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

 Signed informed consent
 Age 50-75 years
 Diagnosis AD in early phase according to the IWG-2 criteria (42)
 In-vivo evidence of Alzheimer´s pathology (one of the following):
o Decreased Aβ42 together with increased t-tau or p-tau in CSF
 Increased tracer retention on amyloid PET
 Mini-Mental State Examination (MMSE) Score ≥20
 Availability of a next of kin who knows the patient well and is willing to accompany the subject
to all trial visits and give information about the patient’s functional level
 The patient is judged fit for the study and capable to cooperate in treatment and follow-up.
 Ability to communicate in Norwegian or another Scandinavian language

- Kvinner og menn i alderen 50-75 år med MCI/tidlig AD.
- Mini-Mental State Examination (MMSE) score ≥20.
- Har pårørende som kjenner pasienten godt og kan følge pasienten til alle konsultasjoner.
- Kommunisere på skandinavisk språk

E.4

Principal exclusion criteria

Patients will be excluded from the study if they meet any of the following criteria:
 Pregnancy or unwilling to use adequate birth control for the duration of and 6 months beyond
study participation. Defined according to Clinical Trial Facilitation Group document
“Recommendations related to contraception and pregnancy testing in clinical trials”
 Positive for Hepatitis B, Hepatitis C or HIV at screening
 Not qualified to give consent at inclusion
 Any other condition judged to interfere with the safety of the patient or the intent and conduct
of the study

Related to medical history:
 Stroke
 Anaphylaxis
 Prior adverse reaction to any human blood product
 Any history of a blood coagulation disorder or hypercoagulability
 Congestive heart failure, defined as any previous heart failure hospitalization, or current
symptomatic heart failure in New York heart Association class ≥II with reduced, mid-range or
preserved ejection fraction
 Coagulation defect or hypercoagulopathy
 Uncontrolled hypertension
 Renal failure
 Prior intolerance to intravenous fluids
 Recent history of uncontrolled atrial fibrillation
 Bone marrow transplant
 IgA deficiency
 Severe protein S deficiency
 Thrombocytopenia (platelets < 40 x 109/L)
 Contraindication for Octaplasma

Related to medications or other treatments:
 Any concurrent use of anticoagulant therapy, clopidogrel or acetylsalicylic acid/dipyridamole
in combination
 Initiation or change in the dosage of a acetylcholine esterase inhibitor (AChEI) or memantine
during the trial (week 0-52). Participants will be urged to start on AChEI when diagnosis is
communicated, and must be on a stable dose for at least one month prior to screening
 Concurrent participation in another treatment trial for AD. If there was prior participation, the
last dose of the investigational agent must have been given at least 6 months prior to
screening, except if the patient received placebo medication
 Treatment with any human blood product, including intravenous immunoglobulin, during the
6 months prior to screening or during the trial
 Concurrent daily treatment with benzodiazepines, typical or atypical antipsychotics, long-
acting opioids, or other medications that are judged to interfere with cognition. Intermittent
treatment with short-acting benzodiazepines or atypical antipsychotics may be permitted,
provided that no dose is administered within 72 hours prior to cognitive assessment

Related to magnetic resonance imaging:
 Claustrophobia
 Any metallic surgical implant, like a pacemaker or clip incompatible with MRI
Certain metallic implants like joint prostheses may be permitted, provided that specific manufacturer specifications are available, and that the device is known to be safe for 7T MRI. In case a patient is not eligible for the 7T scanner, the 3T scanner will be used

- Graviditet eller utilstrekkelig prevensjon mens studien pågår
- Positiv testing for hepatitt B, hepatitt C eller HIV ved screening
- Annen tilstand/situasjon som ansvarlig lege vurderer som risikabelt for pasienten og eller for gjennomførelse av studien.
- Ikke samtykkekompetente
- Avansert sykdom som vanskeliggjør deltakelse
Relatert til sykehistorie (tidligere påvist):
- Gjennomgått hjerneslag
- Anafylaksi
- Bivirkninger av humane blodprodukt
- Koagulasjonsdefekter eller hyperkoagulopati
- Hjertesvikt
- Ubehandlet høyt blodtrykk
- Nyresvikt
- Tidligere intoleranse for intravenøs væsketilførsel
- Nyoppstått, ubehandlet atrieflimmer
- Komplett IgA-mangel eller anti-IgA antistoff
Relatert til medikamentbruk og annen behandling
- Antikoagulasjonsbehandling. Platehemmende medisiner (Albyl-E (acetylsalisylsyre)) er tillatt.
- Initiering eller endring i dose av cholinesterasehemmer eller memantine underveis i studien (uke 0-52): Deltakere som allerede er under behandling med cholinesterasehemmer eller memantine må holdes på en stabil dose minimum en måned før screening.
- Samtidig deltakelse i andre behandlingsstudier for Alzheimers sykdom. Ved deltakelse i tidligere studier må det ha gått minimum 6 måneder etter siste dose med behandling.
- Behandling med humane blodprodukter, inkludert intravenøs immunoglobulin, i løpet av de 6 siste månedene før screening og planlagt behandling i løpet av det året pasientene får behandling.
- Samtidig daglig behandling med benzodiazepiner, typiske eller atypiske antipsykotika, langtidsvirkende opioider, eller andre medikamenter som vurderes av ansvarlig lege å påvirke kognitiv funksjon.
- Intermitterende behandling med korttidsvirkende benzodiazepiner eller atypiske antipsykotika kan tillates, forutsatt at ingen dose administreres innen 72 timer før kognitive tester.
Relatert til MR:
- Klaustrofobi
- Metalliske implantater som pacemaker eller annet som er uforenelig med 3T MRI.

E.5 End points

E.5.1

Primary end point(s)

Number of patiens with adverse events as a measure of safety and tolerability

Antall pasienter med alvorlige hendelser som et mål på sikkerhet og tolerabilitet

E.5.1.1

Timepoint(s) of evaluation of this end point

1 year

1 år

E.5.2

Secondary end point(s)

- Number of subjects who comply with the research protocol as a measure of feasibility
• Change on the Mini-Mental State Examination Score
• Change on the Trail-Making test A and B
• Change on the Clock Drawing Test, COWAT FAS, VOSP, Ten Word Test
• Change on Gait test (GAITRite)
• Change on functional connectivity assessed by resting state functional MRI
• Change in quality of Life SF-36 Questionnaire
• Analysis of biomarkers in blood and cerebrospinal fluid

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 2 and 5 years

1, 2 og 5 år

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

Adverse event evaluated by safety comittee or LVLS

Alvorlig hendelse vurdert av sikkerhetskomitee eller LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Patients with terminal illness

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

Participants will be offered to be retested (without any more treatment) on all parameters 1 year after study intervention is completed for comparison.

For alle som deltar i studien vil alle tester også tilbys etter 2 år for sammenligning (1 år etter endt intervensjonsperiode).

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-05-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-14

P. End of Trial
P.	End of Trial Status	Ongoing

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