Clinical Trials Register

Summary
EudraCT Number:	2014-002524-27
Sponsor's Protocol Code Number:	14-285
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-12-18
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

Netherlands - Competent Authority

A.2

EudraCT number

2014-002524-27

A.3

Full title of the trial

A randomized, placebo-controlled, double blind, 4-period, cross-over trial, to study blood pressure lowering effects of losartan, Moxonidine and Low sodium diet in former pre-eclamptic women

A.3.1

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

The PALM-study (Placebo, Losartan, Low sodium & Moxonidine after PE)

A.3.2

Name or abbreviated title of the trial where available

PALM study

A.4.1

Sponsor's protocol code number

14-285

A.5.4

Other Identifiers

Name:

CCMO

Number:

NL49102.041.14

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	University Medical Center Utrecht
B.1.3.4	Country	Netherlands
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	ZonMw
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Utrecht
B.5.2	Functional name of contact point	Study Principal Investigator
B.5.3	Address:
B.5.3.1	Street Address	Lundlaan 6
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3508AB
B.5.3.4	Country	Netherlands
B.5.6	E-mail	a.t.lely@umcutrecht.nl

D. IMP Identification
D.IMP: 1
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	Losartankalium
D.2.1.1.2	Name of the Marketing Authorisation holder	Mylan B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 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	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	Moxonidine
D.2.1.1.2	Name of the Marketing Authorisation holder	Centrafarm B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 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

Post Partum Hypertension after preeclamptic pregnancy

E.1.1.1

Medical condition in easily understood language

Post Partum Hypertension after preeclamptic pregnancy

E.1.1.2

Therapeutic area

Body processes [G] - Physiological processes [G07]

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

To compare mean 24-hour, day- and night time systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with a history of PE after 8 weeks of treatment with placebo, losartan, moxonidine and low sodium diet in order to identify the physiological processes underlying post partum hypertension.

E.2.2

Secondary objectives of the trial

To compare changes in the following parameters in women with a history of PE after 8 weeks of treatment with placebo, losartan, moxonidine and low sodium diet: RAAS-activity, SNS-activity, endothelial function, arterial stiffness, lipid metabolism, insulin sensitivity, oxidative stress and systemic inflammation.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient is a female between 18 and 45 years of age on the day of signing informed consent.
2. Have a recent history of preeclampsia that is defined as gestational hypertension and concomitant proteinuria in the second half of pregnancy. Gestational hypertension was defined according to the criteria of the International Society for the Study of Hypertension in Pregnancy (ISSHP) as diastolic blood pressure above 90 mmHg and/or systolic blood pressure above 140 mmHg, measured on two or more separate occasions at least 4 hours apart. Proteinuria was diagnosed with urinary protein was above 300 mg per 24 hour or above 2+ at dipstick urinalysis 17
3. All patients should fulfil the following diagnostic criterion:
- Off treatment SBP > 120 mmHg and/or DBP > 80 mmHg during both visits.
4. Blood pressure is assessed by office readings in accordance with current guidelines for hypertension diagnosis18. The patient needs to be seated some minutes before and during the measurement. The cuff size should be adjusted to the patients’ arm circumference and needs to be on the same height level as the patients’ sternum during the measurements. Blood pressure is determined to a 2-mmHg accuracy-level. Blood pressure is measured on both arms during the first visit. If both measurements differ more than 10 mmHg, the highest value is taken. After at least 15 seconds, the measurement is repeated during the same visit. The highest mean of the two measurements on the same arm is considered as the actual blood pressure value.
5. Patient understands the study procedures, alternative treatments available, and risks involved with the study and voluntarily agrees to participate by giving written informed consent.

E.4

Principal exclusion criteria

1. SBP > 180 mmHg and/or DBP > 110 mmHg during one or more screening measurements.
2. Current pregnancy
3. Current smoking or smoking during the previous 3 months
4. Use of “recreational” or illicit drugs
5. Recent history (within the last year) of alcohol abuse or dependence.
6. History of hypersensitivity reactions or intolerance to any (components of) medication used in this trial.
7. Current / recent participation (within 30 days of signing informed consent) in a study with an investigational compound or device.
8. Laboratory values as listed below:
a. Hemoglobin (Hb) < 8,6 mmol/L
b. TSH <0.3 mcIU/mL or > 5.0 mcIU/mL
c. MDRD < 60 mL/min/1,73m2
9. Medical conditions as listed below:
a. Resistant hypertension (blood pressure above target level, despite 3 antihypertensives, including a diuretic)
b. Secondary hypertension
c. Congestive Heart Failure
d. Atherosclerotic vascular disease. (As per NCEP ATP III and AHA/ACC Guidelines: Established atherosclerotic vascular disease includes history of myocardial infarction, stable angina, coronary artery procedures (angioplasty or bypass surgery) or evidence of clinically significant myocardial ischemia. Other atherosclerotic vascular disease includes clinical manifestations of non-coronary forms of atherosclerotic disease (peripheral arterial disease, cerebrovascular disease, abdominal aortic aneurysm, and carotid artery disease [transient ischemic attacks or stroke of carotid origin or >50% obstruction of a carotid artery]).
e. Cardiac arrhythmia’s, for example bradycardia, atrial fibrillation, sick-sinus syndrome, sinoatrial block, atrioventricular block or any other arrhythmia.
f. Obstructive sleep apnea syndrome (OSAS) or a score of 10 or higher on the Epworth Sleepiness Scale questionnaire 19 (see: appendix)
g. Serious liver function disorders (Child-Pugh-Class C).
h. COPD (GOLD classification of severity 2 or higher)
i. Celiac disease or other significant intestinal malabsorption
j. Malignancy ≤ 5 years prior to signing informed consent, except for adequately treated basal or squamous cell skin cancer or in situ cervical cancer.
k. Mental instability or major psychiatric illness
l. Polyneuropathy or clinical suspicion for autonomic nervous system dysfunction.
m. Any diseases that would limit or complicate study evaluation or participation.
n. Any diseases or screening abnormalities that call for treatment that cannot be postponed until after the study period without causing harm.
10. Any concomitant medication, particularly antihypertensive co-medication, glucose lowering medication, lipid lowering drugs, systemic corticosteroids and vitamin C or E supplements, but also any other kinds of drugs, including over the counter medication. Exceptions can be made for the following categories of drugs:
a. paracetamol;
b. proton-pump inhibitors;
c. topical creams and unguents that do not lead to significant uptake of the active components into the circulation (in case of steroid creams: class II or lower);
d. inhalation medication, nasal sprays and eye drops that do not lead to uptake of any of the active components into the circulation.

E.5 End points

E.5.1

Primary end point(s)

Mean 24 hr bloodpressure

E.5.1.1

Timepoint(s) of evaluation of this end point

After each treatment block of 8 weeks

E.5.2

Secondary end point(s)

RAAS-activity, SNS-activity, endothelial function, arterial stiffness, lipid metabolism, insulin sensitivity, oxidative stress and systemic inflammation.

E.5.2.1

Timepoint(s) of evaluation of this end point

After each treatment block of 8 weeks

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

E.6.4

Safety

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

Yes

E.6.13.1

Other scope of the trial description

To identify the physiology of post partum hypertension.

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.1.7

Other

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

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

The end of the trial is two weeks after the last subject finished the final treatment block.

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

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

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

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

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)

Normal treatment will commence after 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

2014-12-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-18

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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