Clinical Trials Register

Summary
EudraCT Number:	2019-003386-18
Sponsor's Protocol Code Number:	CandMigIII
National Competent Authority:	Estonia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-09-22
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

Estonia - SAM

A.2

EudraCT number

2019-003386-18

A.3

Full title of the trial

CandMig III study
Candesartan for migraine prevention:
A multicentre, binational, triple blind, placebo controlled, parallel group study of two doses of candesartan (8 and 16 mg)

A.3.1

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

CandMig III study
A scientific trial of candesartan in two diffeent doses (8 and 16 mg) as a drug for migraine prevention

A.3.2

Name or abbreviated title of the trial where available

CandMig III

A.4.1

Sponsor's protocol code number

CandMigIII

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	Department of Neurology and Clinical Neurophysiology, St Olavs Hospital, Trondheim University hospital
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	The Research Council of Norway
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	Department of Neuromedicine and Movement Science, NTNU- The Norwegian University of Science and Technology
B.5.2	Functional name of contact point	Headache research group
B.5.3	Address:
B.5.3.1	Street Address	NTNU, Faculty of Medicine and Health Sciences
B.5.3.2	Town/ city	Trondheim
B.5.3.3	Post code	N-7491
B.5.3.4	Country	Norway
B.5.4	Telephone number	+4773592020
B.5.6	E-mail	kontakt@inb.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	Yes
D.2.1.1.1	Trade name	Candesartan cilexetil
D.2.1.1.2	Name of the Marketing Authorisation holder	Krka D.D.
D.2.1.2	Country which granted the Marketing Authorisation	Norway
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	Candesartan cilexetil
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	candesartan cilexetil
D.3.9.3	Other descriptive name	Candesartan cilexetil
D.3.9.4	EV Substance Code	SUB13222MIG
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	16
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	Yes
D.2.1.1.1	Trade name	Candesartan cilexetil
D.2.1.1.2	Name of the Marketing Authorisation holder	Krka D.D.
D.2.1.2	Country which granted the Marketing Authorisation	Norway
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	Candesartan cilexetil
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	Candesartan cilexetil
D.3.9.3	Other descriptive name	CANDESARTAN CILEXETIL
D.3.9.4	EV Substance Code	SUB13222MIG
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	8
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
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

Episodic migraine with and without aura

E.1.1.1

Medical condition in easily understood language

Migraine headaches

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	HLT
E.1.2	Classification code	10027603
E.1.2	Term	Migraine headaches
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

Can the favourable effect of candesartan 16 mg, seen in the two smaller single-centre crossover studies be confirmed in a larger parallel group multicentre and binational study?

E.2.2

Secondary objectives of the trial

2) Is there any effect of a daily dose of 8 mg, half of what has been used in the two previous studies? 3) Is the favourable side effect profile, seen in the previous studies, replicated in this larger study, and is it even better with a daily dose of 8 mg as compared to 16 mg? 4) What is the cost of candesartan treatment, considering cost of the medicine, of acute medicines for attacks, and lost worktime.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age 18 to 64 years
2. Signed informed consent
3. Episodic migraine with or without aura according to ICHD-3 criteria(17)
4. At inclusion, patients should retrospectively have from 2 to 8 migraine attacks per month during the last 3 months. This frequency must be confirmed in the headache diary before randomisation to treatment .
5. Debut of migraine at least one year prior to inclusion
6. Start of migraine before age 50 years.
7. No use of other migraine prophylactics during the study
8. For women of child-bearing potential (WOCBP) there must be no pregnancy or planned pregnancy during the study period, and use of highly effective contraception .
After the baseline period, just before randomisation to the study drug, inclusion criteria will be evaluated once more, and the headache diary will be evaluated. If there are, according to the headache diary, fewer attacks than 2 or more than 8 per month, the baseline period can be extended to 8 weeks, and the patient can be randomized to a treatment then if there is a mean of 2-8 attacks per 4 weeks during the 8-week’s period.
In WOCBP, a pregnancy test in the urine must be performed before start of the treatment period. The women can proceed in the study only if the test is negative.

E.4

Principal exclusion criteria

1) Interval headache not distinguishable from migraine;
2) 2) Chronic migraine, chronic tension-type headache, medication overuse headache or other headache occurring on ≥ 15 days/month
3) Pregnancy, planning to get pregnant, nursing or inability to use contraceptives (See inclusion criteria, point 7)
4) Clinical information on or signs of cholestasis or decreased hepatic or renal function. If in doubt, relevant blood tests should be performed (See 4.2.3)
5) High degree of comorbidity and/or frailty associated with reduced life expectancy or high likelihood of hospitalization , at the discretion of the investigator
6) Hypersensitivity to candesartan
7) History of angioneurotic edema
8) Current use of antihypertensive medication
9) Current use of potassium supplements
10) Current use of spironolactone
11) Primary hyperaldosteronism (Conn’s syndrome)
12) Significant psychiatric illness
13) Use of medicines for migraine prophylaxis less than 4 weeks, or of botulinum toxin less than 16 weeks, prior to start of study
14) Having tried ≥ 3 prophylactic drugs against migraine during the last 10 years
15) Previous use of candesartan
16) Requiring detoxification from acute medication (triptans, opioids)
17) Consistently failing to respond to any acute migraine medication
18) Alcohol or illicit drug dependence.
19) Inability to understand study procedures and to comply with them for the entire length of the study

E.5 End points

E.5.1

Primary end point(s)

Difference Number of migraine days per 4 weeksbetween groups receiving candesartan 16 mg daily and placebo in change from baseline in number of migraine days per 4 weeks.

Migraine days are defined as days with moderate or severe headache accompanied by nausea, and/or phono- and photophobia, and lasting ≥ 4 hours or is treated with the patient’s usual migraine medication (usually a triptan).

E.5.1.1

Timepoint(s) of evaluation of this end point

In each patient, this will be evaluated after 12 weeks' treatment

E.5.2

Secondary end point(s)

1. Difference between groups receiving candesartan 8 mg daily and placebo in change from baseline in number of migraine days per 4 weeks.

Per 4 weeks, difference in change from baseline between groups receiving candesartan 16 mg daily and placebo in number of:
2. Days with headache (defined by headache intensity > 0 and/ or intake of the patient’s acute headache medication)
3. Hours with headache
4. Doses of analgesics
5. Doses of triptans
6. Days with sick leave
In addition:
7. Headache intensity (0-3 scale) on days with headache
8. Number of responders (≥ 50% decrease in migraine days compared with baseline)
9. Number of reported side effects
10. Health economic analysis: Comparison of cost in the placebo and candesartan treatment groups, taking into consideration price of the medicine, price of acute medication, and lost worktime.

Per 4 weeks, difference in change from baseline between groups receiving candesartan 8 mg daily and placebo in number of:
11. Days with headache (defined by headache intensity > 0 and/ or intake of the patient’s acute headache medication)
12. Hours with headache
13. Doses of analgesics
14. Doses of triptans
15. Days with sick leave

In addition:
16. Headache intensity (0-3 scale) on days with headache
17. Number of responders (≥ 50% decrease in migraine days compared with baseline)
18. Number of reported side effects
19. Health economic analysis: Comparison of cost in the placebo and candesartan treatment groups, taking into consideration price of the medicine, price of acute medication, and lost worktime.

E.5.2.1

Timepoint(s) of evaluation of this end point

In each patient, this will be evaluated after 12 weeks' treatment. Side effect will in addition be evaluated twice during the treatment period

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

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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

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

Triple blind (Statistician also blinded)

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Estonia

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

Clinical Research Unit,
St Olav’s hospital, Trondheim University hospital

Forskningsavdelingen@stolav.no
postbox 3250 Torgarden, Norway

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

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)

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

Yes

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

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

378

F.4.2.2

In the whole clinical trial

450

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 follow-up is planned in patients without complications, but patients will be offered ordinary health services fitted to the seriousness of their headache condition. However, all ongoing (S)AEs will be followed-up at least until at least 30 days after last IMP administration, resolve or return to baseline value.

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

2020-12-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-15

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

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