Clinical Trials Register

Summary
EudraCT Number:	2013-002126-23
Sponsor's Protocol Code Number:	APOCT-002
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-07-12
Trial results	View 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

Sweden - MPA

A.2

EudraCT number

2013-002126-23

A.3

Full title of the trial

A randomized, double blind, placebo controlled trial to evaluate the safety and efficacy of Apovir for treatment of patients with Alzheimer’s disease

En randomiserad, dubbelblind, placebokontrollerad studie för att utvärdera säkerhet och effekt av Apovir vid behandling av patienter med Alzheimers sjukdom

A.3.1

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

Safety and efficacy of Apovir for treatment of patients with Alzheimer's disease

Säkerhet och effekt av Apovir vid behandling av patienter med Alzheimers sjukdom

A.4.1

Sponsor's protocol code number

APOCT-002

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	Apodemus AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Apodemus AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Apodemus AB
B.5.2	Functional name of contact point	Clinical trials
B.5.3	Address:
B.5.3.1	Street Address	Nobels Väg 3
B.5.3.2	Town/ city	Solna
B.5.3.3	Post code	171 65
B.5.3.4	Country	Sweden
B.5.4	Telephone number	4686197171
B.5.6	E-mail	bo.niklasson@apodemus.se

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	Yes
D.2.1.1.1	Trade name	Copegus
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	ribavirin
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide
D.3.9.1	CAS number	36791-04-5
D.3.9.3	Other descriptive name	RIBAVIRIN
D.3.9.4	EV Substance Code	SUB10297MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	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	pleconaril
D.3.2	Product code	APO-P001
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PLECONARIL
D.3.9.1	CAS number	153168-05-9
D.3.9.2	Current sponsor code	APO-P001
D.3.9.4	EV Substance Code	SUB09957MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Alzheimer's disease

E.1.1.1

Medical condition in easily understood language

Alzheimer's disease

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10001896
E.1.2	Term	Alzheimer's disease
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Main efficacy objective:• To investigate the effect of Apovir on disease progression of AD as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale [ADAS-cog] compared to placebo
Main safety objective: • To investigate the safety and tolerability of the combination therapy of Apovir in patients with AD

E.2.2

Secondary objectives of the trial

• To investigate the effect of Apovir on disease progression of AD assessed by cognitive tests – (Mini Mental State Examination [MMSE], ADAS-cog, Alzheimer’s Quick Test [AQT] and Clinical Dementia Rating [CDR])
• To investigate the plasma and cerebrospinal fluid concentrations of Apovir (APO-P001 and ribavirin) in patients with AD

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients diagnosed with AD according to ICD-10
2. 60–85 years at the time of screening
3. Mini Mental State Exam score 21–27 and judged by the Investigator to be able to give informed consent
4. Patients have adequate hearing, vision, and language skills to perform neuropsychiatric testing and interviews as specified in the protocol, as judged by the Investigator
5. 12-lead ECG with normal tracings; or changes that are not clinically significant and do not require medical intervention, as judged by the Investigator
6. Patient has a relative or caregiver, judged to be reliable by the Investigator, who has signed informed consent. The relative or caregiver should participate in the patient’s visits at the clinic and assist the patient with drug compliance.
7. Willingness to participate after signing informed consent

E.4

Principal exclusion criteria

1. Active hepatitis B, active hepatitis C, or HIV infection
2. Serious cardiac disease including unstable or uncontrolled cardiac disease during the last 6 months and/or previous history of deep vein thrombosis or clinical signs of deep venous thrombosis
3. Major surgical procedure within 4 weeks prior to inclusion
4. Patients on unstable treatment with AChI and / or Memantine for dementia. Unstable treatment is defined as initiated treatment or changed treatment or dose within 3 months prior to the baseline visit (i.e. patients on stable AChI / Memantine treatment and patients without AChI / Memantine treatment can be included in the trial) If patients receive treatment with AChI for dementia this treatment should have been unchanged regarding drug(s) and dose(s) for at least 3 months prior to the baseline visit (patients on an unchanged AChI dose/medication and patients without AChI treatment can be included in the trial)
5. Men without reliable contraceptive method if sexually active with WOCBP. For purposes of this trial, WOCBP include any female who has experienced menarche, who has not undergone tubal ligation, and who is not postmenopausal. Post menopause is defined as: amenorrhea ≥ 12 consecutive months without another cause.
6. Participation in any other clinical trial within 30 days of inclusion (randomisation) in the trial or patients with unresolved investigational treatment-related adverse events
7. Other chronic disease or previous organ transplantation judged by the Investigator to interfere with the assessment of treatment success and/or ability to fully participate in the trial
8. Impaired kidney function with a glomerular filtration rate (GFR) calculated from cystatin C <60 mL/min
9. Calculated ribavirin dose at screening is <600 mg/day* according to the following formula:
0.244 x 10ax 24b x (0.122 x GFR + 0.0414 x body weight in kg)
when a Target concentration=10 mmol/L and b Dosing frequency=24 hours
* If the ribavirin/placebo starting dose is adjusted to 400mg/day the calculated ribavirin dose may be <600mg/day, but must not be <400mg/day at screening.
10. Known blood disease or Anaemia Haemoglobin < 120g/L for women and <130 g/L for men
11. Known haemoglobinopathy (e.g. thalassemia and sickle cell anaemia)
12. Patients that require immunosuppressive treatments including azathioprin, ciclosporin, systemic steroid treatment (e.g. prednisolone at doses of ≥10 mg/day or hydrocortisone) or has received such treatment within the last 6 months prior to randomization
13. Patients that are treated with drugs that can interact significantly with APO-P001; ethinylestradiol and/or ribavirin; azathiopin, didanosine, zidovudine, mercaptopurine, stavudine
14. Lack of suitability for participation in the trial, for any reason, as judged by the Investigator

E.5 End points

E.5.1

Primary end point(s)

Main efficacy endpoint:• ADAS-cog at 9 months (visit 7)
Main safety endpoint: • Frequency and intensity of adverse events

E.5.1.1

Timepoint(s) of evaluation of this end point

Efficacy endpoint: at 9 months
Safety endpoint: total duration of the original part of the trial (visits 1 to 8)

E.5.2

Secondary end point(s)

• Tolerability of Apovir as assessed by dose adjustments, interruption- or discontinuation of treatment
• Vital signs, laboratory parameters and weight
Change in disease progression of AD as assessed by:
• ADAS-cog at 3 months (visit 5), and 6 months (visit 6) and the 1-month follow-up visit (visit 8)
• AQT at 3 months (visit 5), 6 months (visit 6), and 9 months (visit 7) and the follow-up visit
• MMSE at 6 months (visit 6), and 9 months (visit 7) and the follow-up visit
• CDR sum of boxes at 9 months (visit 7) and the follow-up visit
Plasma concentrations of Apovir:
• Plasma concentrations Cpre dose of Apovir (APO-P001 and ribavirin respectively) on day 28 (visit 4) and at 3 months (visit 5), 6 months (visit 6) and 9 months (visit 7) (concentrations at 3 months will be compared to published data [Rhodes and Liu 2001; Khakoo et al 1998])
Cerebrospinal fluid concentrations of Apovir:
• Cerebrospinal fluid concentrations of Apovir (APO-P001 and ribavirin respectively) at 9 months (visit 7)

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoints of evaluation of all safety endpoints is total duration of the original part of the trial (visits 1 to 8).
Timepoints for evaluation of efficacý endpoints is listed in the respective endpoint

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

randomisation will be stratified based on treatment with acetylcholine esterase inhibitors.

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

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

Yes

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

Last patient last visit in the trial

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 dementia of mild severity will be included in the trial.

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

No treatment will be provided to the patients after the end of the trial

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

2013-09-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-06-23

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