Clinical Trials Register

Summary
EudraCT Number:	2013-004866-33
Sponsor's Protocol Code Number:	CA-BP13
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-01-29
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

Sweden - MPA

A.2

EudraCT number

2013-004866-33

A.3

Full title of the trial

A short term open, randomized cross over trial trial exploring the effect of carbonic anhydrase inhibition by acetazolamide on sleep apnea associated hypertension

Blodtryckssänkande effekten av karbanhydrashämning hos patienter med sömnapnérelaterad hypertension.

A.3.1

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

A short term open, randomized cross over trial trial exploring the effect of carbonic anhydrase inhibition by acetazolamide on sleep apnea associated hypertension

Blodtryckssänkande effekten av karbanhydrashämning hos patienter med sömnapnérelaterad hypertension.

A.3.2

Name or abbreviated title of the trial where available

carbonic anhydrase inhibition- sleep apnea associated hypertension

karbanhydrashämning -sömnapnérelaterad hypertension

A.4.1

Sponsor's protocol code number

CA-BP13

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	Göteborgs Universitet
B.1.3.4	Country	Sweden
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	Göteborgs Universitet
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	Göteborgs Universitet
B.5.2	Functional name of contact point	Jan Hedner
B.5.3	Address:
B.5.3.1	Street Address	Medicinaregatan 8b
B.5.3.2	Town/ city	Göteborg
B.5.3.3	Post code	40530
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+46(0)3134210007199
B.5.6	E-mail	jan.hedner@lungall.gu.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	DIamox
D.2.1.1.2	Name of the Marketing Authorisation holder	Mercury Pharmaceuticals Ltd , No 1 Croydon, 12-16 Addiscombe Road , Croydon CR0 0XT, Storbritannien
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	Diamox
D.3.4	Pharmaceutical form	Tablet
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	Acetazolamide
D.3.9.1	CAS number	59-66-5
D.3.9.3	Other descriptive name	ACETAZOLAMIDE
D.3.9.4	EV Substance Code	SUB05219MIG
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	750
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

obstructive sleep apnea related hypertension

obstruktiv sömnapné relaterad hypertension

E.1.1.1

Medical condition in easily understood language

obstructive sleep apnea related hypertension

obstruktiv sömnapné relaterad hypertension

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10055577
E.1.2	Term	Obstructive sleep apnea syndrome
E.1.2	System Organ Class	100000004855

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 primary objective of this study is to use the enzyme carbonic anhydrase (CA) well known properties in order to create a physiological condition in order to explore and compare the efficacy of pharmacological CA inhibition on obstructive sleep apnea (OSA) related hypertension. Multiple aspects of vascular function and blood pressure control will be investigated in 12 male patients, using non-invasive methods, before and after short-term treatment of the carbonic anhydrase system (by acetazolamide (ACZ), continuous positive airway pressure (nCPAP) and nCPAP plus ACZ

I aktuell studie är syftet att utnyttja enzymet karbanhydras kända egenskaper för att skapa ett fysiologiskt tillstånd i syfte att studera och jämföra effekten av farmakologisk karbanhydrashämning hos patienter med OSA-relaterad hypertoni. Försökspersonerna kommer att undersökas med avseende på blodtryck, hemodynamiska samt sömnapné-variabler, före och efter behandling med acetazolamid, CPAP (kontinuerlig luftvägsövertryck, konventionell behandling av OSA) samt CPAP och acetazolamid genom icke- invasiva tester.

E.2.2

Secondary objectives of the trial

The secondary objective is to investigate the direct effect of CA inhibition on sleep disordered breathing.

Sekundärt vill vi även undersöka effekten av karbanhydrashämning på sömnapné.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of informed consent prior to any study specific procedures
2. Males 18 to 75 years
3. An Apnea-Hypopnea Index (AHI)>15 and an Epworth Sleepiness Scale score (ESS)>6 as verified by a PSG recording.
4. Patients with established hypertension (systolic/diastolic blood pressure >= 160/95, either systolic or diastolic accounted for).
5. Clinically normal physical findings and laboratory values, as judged by the investigator
6. Body mass index >= 35 kg/m2

E.4

Principal exclusion criteria

1. Hypersensitivity to sulfonamides or acetazolamide.
2. Patients with ongoing medication with other sulphonamides or patients any specific antihypertensive treatment.
3. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity.
4. Subjects with a seizure disorder.
5. Patients with clinically verified central sleep apnea.
6. Clinically significant renal (serum creatinine >2.0 mg/dL or >130 mol/L), neurological, metabolic (e.g. Type 1 or 2 diabetes), haematological or hepatic disease (ASAT or ALAT >2 times the upper limit of normal).
7. Subjects with an occupational risk potentially exaggerated by daytime sleepiness such as handling complex machinery or professional driving.
8. Unstable angina pectoris, unstable hypertension (or poorly controlled diabetes (HbA1C < 52 mmoles/mol, or fasting plasma glucose >7 mmoles/l).
9. Clinically significant congestive heart failure.
10. Myocardial infarction or coronary vessel intervention within the previous 6 months period.
11. Subjects with uncontrolled hypertension (defined as a diastolic blood pressure 110 mmHg and/or a systolic blood pressure ≥180 mmHg with or without medication).
12. Previously diagnosed or treated clinically significant cardiac arrhythmia.
13. Clinically significant chronic pulmonary or gastrointestinal disease.
14. Clinical history of depression as judged by the investigator or other previous or present clinically significant psychiatric disease.
15. Suspected or confirmed poor compliance.
16. Alcohol or drug abuse during the last year.
17. Subjects with any other significant condition that, in the opinion of the investigator, could interfere with participation in the study.
18. Severe nocturnal hypoxia defined as more than 10 episodes with an oxygen desaturation exceeding 50% or signs of lacking resaturation between desaturations on previous recordings according to investigators judgment.
19. Participation in another clinical study during the last 6 months-
20. Inability to understand and complete the questionnaires.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint will be expressed in terms systolic and diastolic blood pressure (resting office, provoked office and 24 hour) as well as in various terms of vascular function (overnight vascular stiffness, heart rate variability and hypoxic vascular responsiveness) when comparing the acetazolamide to the nCPAP plus acetazolamide treatment regimen.

E.5.1.1

Timepoint(s) of evaluation of this end point

The total study period is 10 weeks. Endpoint will be evaluated between baseline (0 weeks) and at end of each treatment period. Each treatment period is 2 weeks with a wash-out period between treatment regimens.

E.5.2

Secondary end point(s)

The change in sleep disordered breathing variables such as Apnea-Hypopnea index score (AHI), oxygen desaturation index (ODI), mean overnight oxygenation, and sleep quality, daytime sleepiness, patient-reported outcomes, and effects on metabolic markers when comparing treatment regimens.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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

This is a hypothesis-generating research study, a methodological study.

Detta är en hypotes-genererande och metodologisk studie.

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Continuous positive airway pressure (CPAP), and CPAP plus acetazolamide.

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

Study is defined as complete ("end of study") when the last patient completes the final study day.

Studien definieras som klar ("slut") när den sista patienten genomgått sista studiedagen.

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)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

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

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)

Patients will be followed up according to clinical routines within the health sector after the study is completed.

Patienterna kommer efter att de blivit avslutad i studien att behandlas på sedvanligt sätt enligt kliniska rutiner inom sjuk-och hälsovården.

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

2014-03-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-04

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

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