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Clinical Trial Results:
Antihypertensive effect of different doses of ROSTAFUROXIN in comparison with Losartan, assessed by office and ambulatory blood pressure monitoring in a hypertensive population selected according to a specific genetic profile.

Summary
EudraCT number	2010-022073-34
Trial protocol	IT
Global end of trial date	08 Feb 2018

Results information
Results version number	v1(current)
This version publication date	19 Sep 2020
First version publication date	19 Sep 2020
Other versions
Summary report(s)	Antihypertensive effect of rostafuroxin in comparison with losartan, by office and ambulatory blood pressure monitoring in a hypertensive population selected according to a specific genetic profile

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

PST2238-DM-10-001

ISRCTN number

US NCT number

NCT01320397

WHO universal trial number (UTN)

Sponsor organisation name

RostaQuo S.p.A

Sponsor organisation address

Via Pontina Km 30,400, Pomezia (Roma), Italy, 00040

Public contact

Clinical Trials Information, RostaQuo S.p.A, 39 06913942103916, rostaquo@legalmail.it

Scientific contact

Clinical Trials Information, RostaQuo S.p.A, 39 06913942103916, rostaquo@legalmail.it

Sponsor organisation name

CVie Therapeutics Company Limited

Sponsor organisation address

No2. Science Park West Avenue, Shatin, Hong Kong,

Public contact

CVie Therapeutics Company Limited, CVie Therapeutics Company Limited, 852 2314 6572, Wy.lam@leespharm.com

Scientific contact

CVie Therapeutics Company Limited, CVie Therapeutics Company Limited, 852 2314 6572, Wy.lam@leespharm.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Jan 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Feb 2018

Global end of trial reached?

Yes

Global end of trial date

08 Feb 2018

Was the trial ended prematurely?

Main objective of the trial

The two primary objectives are as follows : to demonstrate that the highest two doses of ROSTAFUROXIN (50 microg. and 500 microg.) are able to show a statistically significant difference on reduction of office sitting systolic blood pressure (OSBP) in comparison to the group of patients treated with Losartan 50 mg in either: 1. the total population bearing a mutation included in the Genetic Profile 1 or 2. the subset of patients of Profile 1 carrying only the Genetic Profile 2

Protection of trial subjects

This trial involved a subset of newly discovered and never-treated (naïve) hypertensive patients, at an initial grade 1 type of hypertension, who have been selected according to an OSBP level >140 mmHg and ODBP >85 mmHg, and with normal organ functions. Risks for the patient such as the onset of adverse events that may required the decision on the continuation of the treatment, and the deviation that may affects the validity of the results, were monitored by: Data and Safety Monitoring Board (DSMB) Any adverse event which causes the termination of treatment or serious adverse events experienced by the patients was promptly reported to all members of the committee within 24 hours following time of their acknowledgement by the Sponsor. Case Report Form (CRF) A Run-In and Treatment Period CRF will be prepared for the study, recording all variables mentioned in the Protocol. The forms for registration of possible adverse events, concomitant medications and any suspension of the Study were placed at the end of the CRF. Clinical Monitoring to verify, according to the Sponsor’s requirements, that the study is conducted and documented properly in accordance with the Good Clinical Practice. Audits The Auditor has been appointed by the Sponsor to verify the conduct of the Study, having the possibility to perform audits at the investigational site with direct access to the Trial Master File, Case Report Forms, source documents, informed consent and patients’ hospital records. Inspections The Investigator/Institution allowed Regulatory Authorities, national and foreign, to carry out inspections. Inspections, on part of one or more Regulatory Authorities, consist in an official revising of documents, structures, recordings and any other source said authorities consider as connected to the study.

Background therapy

Evidence for comparator

The choice of losartan, as comparator, is supported by two reasons: 1) since this study included an initial run-in period with lifestyle changes, followed by a subsequent study period of two months, a placebo arms could not have been approved by some Ethical Committees; 2) the just completed SOPHIA study on losartan in naïve patients (Frau, Pharmacogenomics, 2014) whose clinical design is similar to that of the previous OASIS-HT study (Lanzani, Science Translational Medicine, 2010), furnished preliminary data for planning the present PEARL-HT study. Standing the well-established relationship between the body sodium and the pressor response to angiotensin II that increases at higher body sodium, the losartan efficacy may also be potentiated by gene variants that, by increasing renal tubular reabsorption, may enhance body sodium. This limits the validity to assess causation from the difference in the BP response, that may also regard any of the available antihypertensive drugs, acting on physiological mechanisms involved in BP regulation.

Actual start date of recruitment

26 Jun 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Italy: 470

Country: Number of subjects enrolled

Taiwan: 432

Worldwide total number of subjects

902

EEA total number of subjects

470

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

902

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

PEARL-HT clinical trial, phase 2b multicenter, double-blind, double-dummy, four-arms, parallel group, active comparator-controlled study was conducted in newly discovered and never-treated (naïve) hypertensive patients enrolled in 13 Italian centers and in 15 Taiwanese centres, Italy June 2013-January 2016, Taiwan December 2015-December 2017.

Screening details

The eligibility of the naïve hypertensive patients included: age between 25 and 60 years, being carrier of one or a combination of polymorphisms of the genetic profile P1, with at least 50% of the enrolled patients having a combination of gene variants of the original genetic profile P2. Sitting OSBP 140-169 mmHg, ODBP 85-100 mmHg.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Caucasian rostafuroxin 6 microg.

Arm description

Arm type

Experimental

Investigational medicinal product name

rostafuroxin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

6 microg. administered orally as one capsule daily

Caucasian rostafuroxin 50 microg.

Arm description

Arm type

Experimental

Investigational medicinal product name

rostafuroxin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

50 microg. administered orally as one capsule daily

Caucasian rostafuroxin 500 microg.

Arm description

Arm type

Experimental

Investigational medicinal product name

rostafuroxin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

500 microg. administered orally as one capsule daily

Caucasian losartan 50 mg.

Arm description

Arm type

Active comparator

Investigational medicinal product name

losartan

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

50 mg administered orally as one capsule daily

Chinese rostafuroxin 50 microg.

Arm description

Arm type

Experimental

Investigational medicinal product name

rostafuroxin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

50 microg. administered orally as one capsule daily

Chinese rostafuroxin 500 microg.

Arm description

Arm type

Experimental

Investigational medicinal product name

rostafuroxin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

500 microg. administered orally as one capsule daily

Chinese losartan 50 mg.

Arm description

Arm type

Active comparator

Investigational medicinal product name

losartan

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

50 mg administered orally as one capsule daily

Number of subjects in period 1 ^[1]	Caucasian rostafuroxin 6 microg.	Caucasian rostafuroxin 50 microg.	Caucasian rostafuroxin 500 microg.	Caucasian losartan 50 mg.	Chinese rostafuroxin 50 microg.	Chinese rostafuroxin 500 microg.	Chinese losartan 50 mg.
Started	43	43	43	43	35	35	37
Completed	38	35	39	40	33	34	34
Not completed	5	8	4	3	2	1	3
Patient withdrawn without any treatment	-	1	-	-	-	-	-
Lost to follow-up	5	7	4	3	2	1	3

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The number of subjects reported at the baseline period (n=279) is different from the worldwide number enrolled in the trial (n=902) because only subjects carrying the genetic profile were randomized.

Baseline characteristics

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Reporting group title

Caucasian rostafuroxin 6 microg.

Reporting group description

Reporting group title

Caucasian rostafuroxin 50 microg.

Reporting group description

Reporting group title

Caucasian rostafuroxin 500 microg.

Reporting group description

Reporting group title

Caucasian losartan 50 mg.

Reporting group description

Reporting group title

Chinese rostafuroxin 50 microg.

Reporting group description

Reporting group title

Chinese rostafuroxin 500 microg.

Reporting group description

Reporting group title

Chinese losartan 50 mg.

Reporting group description

Reporting group values	Caucasian rostafuroxin 6 microg.	Caucasian rostafuroxin 50 microg.	Caucasian rostafuroxin 500 microg.	Caucasian losartan 50 mg.	Chinese rostafuroxin 50 microg.	Chinese rostafuroxin 500 microg.	Chinese losartan 50 mg.	Total
Number of subjects	43	43	43	43	35	35	37	279
Age categorical
Units: Subjects
Adults (25-60 years)	43	43	43	43	35	35	37	279
Age continuous
Units: years
arithmetic mean (full range (min-max))	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	-
Gender categorical
Units: Subjects
Female	17	18	11	10	16	12	19	103
Male	26	25	32	33	19	23	18	176
OSBP at baseline
Office Systolic Blood Pressure (OSBP) at baseline
Units: mmHg
arithmetic mean (standard deviation)	0 ± 0	0 ± 0	0 ± 0	0 ± 0	0 ± 0	0 ± 0	0 ± 0	-

Subject analysis set title

Caucasian rostafuroxin 6 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 6 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Caucasian rostafuroxin 500 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 500 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Caucasian losartan 50 mg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Chinese rostafuroxin 50 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 50 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Chinese rostafuroxin 500 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 500 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Chinese losartan 50 mg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with losartan 50 mg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Caucasian rostafuroxin 6 microg. - Genetic Profile P2a

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 6 microg. and carrying at least one pair of gene variants included in the genetic profile P2a.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - Genetic Profile P2a

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying at least one pair of gene variants included in the genetic profile P2a.

Subject analysis set title

Caucasian rostafuroxin 500 microg. - Genetic Profile P2a

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 500 microg. and carrying at least one pair of gene variants included in the genetic profile P2a.

Subject analysis set title

Caucasian losartan 50 mg. - Genetic Profile P2a

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying at least one pair of gene variants included in the genetic profile P2a.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - LSS AA

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying LSS AA genotype.

Subject analysis set title

Caucasian losartan 50 mg. - LSS AA

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying LSS AA genotype.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - LSS CC

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying LSS CC genotype.

Subject analysis set title

Caucasian losartan 50 mg. - LSS CC

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying LSS CC genotype.

Subject analysis set title

Caucasian rostafuroxin 6 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 6 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Caucasian rostafuroxin 500 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 500 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Caucasian losartan 50 mg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Chinese rostafuroxin 50 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 50 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Chinese rostafuroxin 500 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 500 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Chinese losartan 50 mg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 500 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis sets values	Caucasian rostafuroxin 6 microg. - Genetic Profile P2	Caucasian rostafuroxin 50 microg. - Genetic Profile P2	Caucasian rostafuroxin 500 microg. - Genetic Profile P2	Caucasian losartan 50 mg. - Genetic Profile P2	Chinese rostafuroxin 50 microg. - Genetic Profile P2	Chinese rostafuroxin 500 microg. - Genetic Profile P2	Chinese losartan 50 mg. - Genetic Profile P2	Caucasian rostafuroxin 6 microg. - Genetic Profile P2a	Caucasian rostafuroxin 50 microg. - Genetic Profile P2a	Caucasian rostafuroxin 500 microg. - Genetic Profile P2a	Caucasian losartan 50 mg. - Genetic Profile P2a	Caucasian rostafuroxin 50 microg. - LSS AA	Caucasian losartan 50 mg. - LSS AA	Caucasian rostafuroxin 50 microg. - LSS CC	Caucasian losartan 50 mg. - LSS CC	Caucasian rostafuroxin 6 microg. - Genetic Profile P1	Caucasian rostafuroxin 50 microg. - Genetic Profile P1	Caucasian rostafuroxin 500 microg. - Genetic Profile P1	Caucasian losartan 50 mg. - Genetic Profile P1	Chinese rostafuroxin 50 microg. - Genetic Profile P1	Chinese rostafuroxin 500 microg. - Genetic Profile P1	Chinese losartan 50 mg. - Genetic Profile P1
Number of subjects	20	17	19	23	14	15	16	16	15	18	20	6	6	9	18	36	35	39	40	30	33	33
Age categorical
Units: Subjects
Adults (25-60 years)	20	17	19	23	14	15	16	16	15	18	20
Age continuous
Units: years
arithmetic mean (full range (min-max))	49.0 (30 to 59)	46.7 (31 to 56)	48.2 (38 to 56)	50.7 (29 to 62)	45.5 (33 to 57)	47.5 (28 to 60)	47.6 (36 to 60)	48.6 (30 to 59)	46.9 (31 to 56)	48.4 (38 to 56)	50.3 (29 to 62)	46.5 (31 to 61)	49.8 (41 to 59)	47.8 (35 to 54)	50.4 (35 to 59)	47.9 (30 to 59)	49.1 (31 to 61)	49.5 (29 to 59)	49.9 (29 to 62)	46.0 (33 to 57)	44.7 (28 to 60)	44.6 (27 to 60)
Gender categorical
Units: Subjects
Female	9	6	5	4	4	4	8	8	6	4	4	3	1	5	2	15	15	10	9	13	11	17
Male	11	11	14	19	10	11	8	8	9	14	16	3	5	4	16	21	20	29	31	17	22	16
OSBP at baseline
Office Systolic Blood Pressure (OSBP) at baseline
Units: mmHg
arithmetic mean (standard deviation)	151.9 ± 6.6	151.4 ± 7.3	151.7 ± 6.5	150.5 ± 8.4	144.7 ± 4.6	145.9 ± 7.4	146.7 ± 8.1	150.7 ± 6.7	151.0 ± 7.7	151.3 ± 6.5	149.8 ± 8.1	153.6 ± 5.4	154.6 ± 7.4	151.8 ± 8.2	150.3 ± 6.1	149.6 ± 6.1	151.2 ± 6.2	150.4 ± 5.9	151.4 ± 7.5	146.5 ± 6.5	146.2 ± 7.2	146.6 ± 7.1

End points

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Reporting group title

Caucasian rostafuroxin 6 microg.

Reporting group description

Reporting group title

Caucasian rostafuroxin 50 microg.

Reporting group description

Reporting group title

Caucasian rostafuroxin 500 microg.

Reporting group description

Reporting group title

Caucasian losartan 50 mg.

Reporting group description

Reporting group title

Chinese rostafuroxin 50 microg.

Reporting group description

Reporting group title

Chinese rostafuroxin 500 microg.

Reporting group description

Reporting group title

Chinese losartan 50 mg.

Reporting group description

Subject analysis set title

Caucasian rostafuroxin 6 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 6 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Caucasian rostafuroxin 500 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 500 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Caucasian losartan 50 mg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Chinese rostafuroxin 50 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 50 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Chinese rostafuroxin 500 microg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 500 microg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Chinese losartan 50 mg. - Genetic Profile P2

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with losartan 50 mg. and carrying at least one pair of gene variants included in the genetic profile P2.

Subject analysis set title

Caucasian rostafuroxin 6 microg. - Genetic Profile P2a

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 6 microg. and carrying at least one pair of gene variants included in the genetic profile P2a.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - Genetic Profile P2a

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying at least one pair of gene variants included in the genetic profile P2a.

Subject analysis set title

Caucasian rostafuroxin 500 microg. - Genetic Profile P2a

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 500 microg. and carrying at least one pair of gene variants included in the genetic profile P2a.

Subject analysis set title

Caucasian losartan 50 mg. - Genetic Profile P2a

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying at least one pair of gene variants included in the genetic profile P2a.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - LSS AA

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying LSS AA genotype.

Subject analysis set title

Caucasian losartan 50 mg. - LSS AA

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying LSS AA genotype.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - LSS CC

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying LSS CC genotype.

Subject analysis set title

Caucasian losartan 50 mg. - LSS CC

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying LSS CC genotype.

Subject analysis set title

Caucasian rostafuroxin 6 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 6 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Caucasian rostafuroxin 50 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 50 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Caucasian rostafuroxin 500 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with rostafuroxin 500 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Caucasian losartan 50 mg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Caucasian subjects treated with losartan 50 mg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Chinese rostafuroxin 50 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 50 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Chinese rostafuroxin 500 microg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 500 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Subject analysis set title

Chinese losartan 50 mg. - Genetic Profile P1

Subject analysis set type

Per protocol

Subject analysis set description

Chinese subjects treated with rostafuroxin 500 microg. and carrying at least one gene variant or one pair of gene variants included in the genetic profile P1.

Primary: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2a adjusted

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End point title

Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2a adjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2a (adjusted for genetic heterogeneity). The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of covariance (ANCOVA) model. Analysis compared the group treated with 6 mcg rostafuroxin versus the group treated with losartan, with the continuous fixed covariate of baseline.

End point type

Primary

End point timeframe

Office Systolic Blood pressure (OSBP) change two months after randomization - Caucasian subjects carrying at least one pair of gene variants included in the genetic profile P2a, mean change adjusted for OSBP at baseline.

End point values	Caucasian rostafuroxin 6 microg. - Genetic Profile P2a	Caucasian losartan 50 mg. - Genetic Profile P2a
Number of subjects analysed	16	20
Units: mmHg
arithmetic mean (confidence interval 95%)	-10.8 (-17.48 to -4.01)	-13.2 (-19.22 to -7.15)

P2a rostafuroxin 6 microg. vs losartan- Caucasian

Statistical analysis description

ANCOVA / Caucasian - 6 microg. rostafuroxin vs. losartan, Per Protocol Set ANCOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 6 microg. - Genetic Profile P2a v Caucasian losartan 50 mg. - Genetic Profile P2a

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.592

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-6.61

upper limit

11.48

Primary: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2a adjusted

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End point title

Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2a adjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2a (adjusted for genetic heterogeneity). The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of covariance (ANCOVA) model. Analysis compared the group treated with 50 mcg rostafuroxin versus the group treated with losartan, with the continuous fixed covariate of baseline.

End point type

Primary

End point timeframe

End point values	Caucasian rostafuroxin 50 microg. - Genetic Profile P2a	Caucasian losartan 50 mg. - Genetic Profile P2a
Number of subjects analysed	15	20
Units: mmHg
arithmetic mean (confidence interval 95%)	-23.0 (-29.91 to -16.0)	-13.2 (-19.22 to -7.15)

P2a rostafuroxin 50 microg. vs losartan- Caucasian

Statistical analysis description

ANCOVA / Caucasian - 50 microg. rostafuroxin vs. losartan, Per Protocol Set ANCOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 50 microg. - Genetic Profile P2a v Caucasian losartan 50 mg. - Genetic Profile P2a

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.038

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-9.8

Confidence interval

level

95%

sides

2-sided

lower limit

-18.99

upper limit

-0.56

Primary: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2a adjusted

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End point title

Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2a adjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2a (adjusted for genetic heterogeneity). The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of covariance (ANCOVA) model. Analysis compared the group treated with 500 mcg rostafuroxin versus the group treated with losartan, with the continuous fixed covariate of baseline.

End point type

Primary

End point timeframe

End point values	Caucasian rostafuroxin 500 microg. - Genetic Profile P2a	Caucasian losartan 50 mg. - Genetic Profile P2a
Number of subjects analysed	18	20
Units: mmHg
arithmetic mean (confidence interval 95%)	-17.4 (-23.74 to -11.03)	-13.2 (-19.22 to -7.15)

P2a rostafuroxin 500 microg. vs losartan-Caucasian

Statistical analysis description

ANCOVA / Caucasian - 500 microg. rostafuroxin vs. losartan, Per Protocol Set ANCOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 500 microg. - Genetic Profile P2a v Caucasian losartan 50 mg. - Genetic Profile P2a

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.342

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-12.98

upper limit

4.57

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS AA adjusted

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End point title

Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS AA adjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the LSS AA genotype. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of covariance (ANCOVA) model. Analysis compared the group treated with 50 mcg rostafuroxin versus the group treated with losartan, with the continuous fixed covariate of baseline.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two months after randomization - Caucasian subjects carrying the LSS AA genotype, mean change adjusted for OSBP at baseline.

End point values	Caucasian rostafuroxin 50 microg. - LSS AA	Caucasian losartan 50 mg. - LSS AA
Number of subjects analysed	6	6
Units: mmHg
arithmetic mean (confidence interval 95%)	-27.3 (-35.79 to -18.89)	-13.9 (-22.33 to -5.43)

LSS AA - rostafuroxin 50 vs losartan - Caucasian

Statistical analysis description

ANCOVA / Caucasian - 50 microg. rostafuroxin and 50 mg losartan treatment arms, LSS AA genotype, Per Protocol Set ANCOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect and baseline as covariate. Treatment difference.

Comparison groups

Caucasian losartan 50 mg. - LSS AA v Caucasian rostafuroxin 50 microg. - LSS AA

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.031 ^[2]

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-13.5

Confidence interval

level

95%

sides

2-sided

lower limit

-25.43

upper limit

-1.49

Notes
[1] - Comparison of OSBP fall (adjusted for OSBP at baseline) between LSS AA carriers treated with rostafuroxin 50 mcg. and LSS AA carriers treated with losartan 50 mg (9 week-treatment).
[2] - Treatment difference (mmHg), 50 microg. rostafuroxin AA - losartan AA, Caucasian.

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS CC adjusted

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End point title

Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS CC adjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the LSS CC genotype. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of covariance (ANCOVA) model. Analysis compared the group treated with 50 mcg rostafuroxin versus the group treated with losartan, with the continuous fixed covariate of baseline.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two months after randomization - Caucasian subjects carrying the LSS CC genotype, mean change adjusted for OSBP at baseline.

End point values	Caucasian rostafuroxin 50 microg. - LSS CC	Caucasian losartan 50 mg. - LSS CC
Number of subjects analysed	9	18
Units: mmHg
arithmetic mean (confidence interval 95%)	-10.3 (-19.51 to -1.13)	-17.7 (-24.14 to -11.17)

LSS CC - rostafuroxin 50 vs losartan - Caucasian

Statistical analysis description

ANCOVA / Caucasian - 50 microg. rostafuroxin and losartan treatment arms, LSS CC genotype, Per Protocol Set ANCOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect and baseline as covariate. Treatment difference.

Comparison groups

Caucasian rostafuroxin 50 microg. - LSS CC v Caucasian losartan 50 mg. - LSS CC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.192 ^[4]

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

7.3

Confidence interval

level

95%

sides

2-sided

lower limit

-3.94

upper limit

18.61

Notes
[3] - Comparison of OSBP fall (adjusted for OSBP at baseline) between LSS CC carriers treated with rostafuroxin 50 microg. and LSS CC carriers treated with losartan 50 mg (9 weeks treatment).
[4] - Treatment difference (mmHg), 50 microg. rostafuroxin LSS CC - losartan LSS CC, Caucasian

Other pre-specified: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2 adjusted

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End point title

Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2 adjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of covariance (ANCOVA) model. Analysis compared the group treated with 6 mcg rostafuroxin versus the group treated with losartan, with the continuous fixed covariate of baseline.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Caucasian subjects carrying at least one pair of gene variants included in the genetic profile P2, mean change adjusted for OSBP at baseline.

End point values	Caucasian rostafuroxin 6 microg. - Genetic Profile P2	Caucasian losartan 50 mg. - Genetic Profile P2
Number of subjects analysed	20	23
Units: mmHg
arithmetic mean (confidence interval 95%)	-8.3 (-14.56 to -2.10)	-13.7 (-19.51 to -7.88)

P2 adj- rostafuroxin 6 microg. vs losartan - Cauca

Statistical analysis description

ANCOVA / Caucasian - 6 microg. rostafuroxin vs. losartan, Per Protocol Set ANCOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 6 microg. - Genetic Profile P2 v Caucasian losartan 50 mg. - Genetic Profile P2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.214

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

5.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.17

upper limit

13.89

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2 adjusted

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End point title

Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2 adjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of covariance (ANCOVA) model. Analysis compared the group treated with 50 mcg rostafuroxin versus the group treated with losartan, with the continuous fixed covariate of baseline.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two months after randomization - Caucasian subjects carrying at least one pair of gene variants included in the genetic profile P2, mean change adjusted for OSBP at baseline.

End point values	Caucasian rostafuroxin 50 microg. - Genetic Profile P2	Caucasian losartan 50 mg. - Genetic Profile P2
Number of subjects analysed	17	23
Units: mmHg
arithmetic mean (confidence interval 95%)	-22.2 (-28.92 to -15.42)	-13.7 (-19.51 to -7.88)

P2 rostafuroxin 50 microg. vs losartan- Caucasian

Statistical analysis description

ANCOVA / Caucasian - 50 microg. rostafuroxin vs. losartan, Per Protocol Set ANCOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 50 microg. - Genetic Profile P2 v Caucasian losartan 50 mg. - Genetic Profile P2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.062

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-8.5

Confidence interval

level

95%

sides

2-sided

lower limit

-17.39

upper limit

0.43

Other pre-specified: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2 adjusted

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End point title

Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2 adjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of covariance (ANCOVA) model. Analysis compared the group treated with 500 mcg rostafuroxin versus the group treated with losartan, with the continuous fixed covariate of baseline.

End point type

Other pre-specified

End point timeframe

End point values	Caucasian rostafuroxin 500 microg. - Genetic Profile P2	Caucasian losartan 50 mg. - Genetic Profile P2
Number of subjects analysed	19	23
Units: mmHg
arithmetic mean (confidence interval 95%)	-19.5 (-25.88 to -13.11)	-13.7 (-19.51 to -7.88)

P2 rostafuroxin 500 microg. vs losartan- Caucasian

Statistical analysis description

ANCOVA / Caucasian - 500 microg. rostafuroxin vs. losartan, Per Protocol Set ANCOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian losartan 50 mg. - Genetic Profile P2 v Caucasian rostafuroxin 500 microg. - Genetic Profile P2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.185

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-5.8

Confidence interval

level

95%

sides

2-sided

lower limit

-14.44

upper limit

2.84

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS AA/CC adjusted

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End point title

Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS AA/CC adjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the LSS AA or LSS CC genotype. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of covariance (ANCOVA) model. Analysis compared the group treated with 50 mcg rostafuroxin versus the group treated with losartan, with the continuous fixed covariate of baseline.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two months after randomization - Caucasian subjects carrying the LSS AA or CC genotype, mean change adjusted for OSBP at baseline.

End point values	Caucasian rostafuroxin 50 microg. - LSS AA	Caucasian losartan 50 mg. - LSS AA	Caucasian rostafuroxin 50 microg. - LSS CC	Caucasian losartan 50 mg. - LSS CC
Number of subjects analysed	6	6	9	18
Units: mmHg
arithmetic mean (confidence interval 95%)	-25.2 (-35.38 to -15.02)	-12.9 (-22.30 to -1.78)	-11.1 (-19.35 to -2.83)	-18.6 (-24.51 to -12.68)

LSS- rostafuroxin 50 microg. vs losartan-Caucasian

Statistical analysis description

ANCOVA / Caucasian - LSS AA or CC - 50 microg. rostafuroxin vs. losartan, Per Protocol Set ANCOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 50 microg. - LSS AA v Caucasian losartan 50 mg. - LSS AA v Caucasian rostafuroxin 50 microg. - LSS CC v Caucasian losartan 50 mg. - LSS CC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.023 ^[5]

Method

ANCOVA

Parameter type

Mean difference (net)

Confidence interval

Notes
[5] - Model analysis of OSBP for LSS AA and CC in Caucasians, 50 mcg Rostafuroxin and Losartan. P value for Treatment x LSS genotype interaction.

Other pre-specified: Chinese OSBP difference between 50 mcg rostafuroxin and Losartan - P2 unadjusted

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End point title

Chinese OSBP difference between 50 mcg rostafuroxin and Losartan - P2 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 50 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Chinese subjects carrying at least one pair of gene variants included in the genetic profile P2, mean change.

End point values	Chinese rostafuroxin 50 microg. - Genetic Profile P2	Chinese losartan 50 mg. - Genetic Profile P2
Number of subjects analysed	14	16
Units: mmHg
arithmetic mean (confidence interval 95%)	-0.2 (-6.15 to 5.73)	-15.4 (-20.96 to -9.85)

P2 - rostafuroxin 50 microg. vs losartan - Chinese

Statistical analysis description

ANOVA/ Chinese - 50 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Chinese rostafuroxin 50 microg. - Genetic Profile P2 v Chinese losartan 50 mg. - Genetic Profile P2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

15.2

Confidence interval

level

95%

sides

2-sided

lower limit

7.06

upper limit

23.32

Other pre-specified: Chinese OSBP difference between 500 mcg rostafuroxin and Losartan - P2 unadjusted

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End point title

Chinese OSBP difference between 500 mcg rostafuroxin and Losartan - P2 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 500 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Chinese subjects carrying at least one pair of gene variants included in the genetic profile P2, mean change.

End point values	Chinese rostafuroxin 500 microg. - Genetic Profile P2	Chinese losartan 50 mg. - Genetic Profile P2
Number of subjects analysed	15	16
Units: mmHg
arithmetic mean (confidence interval 95%)	-4.7 (-10.4 to 1.06)	-15.4 (-20.96 to -9.85)

P2 - rostafuroxin 500 microg. vs losartan- Chinese

Statistical analysis description

ANOVA/ Chinese - 500 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Chinese rostafuroxin 500 microg. - Genetic Profile P2 v Chinese losartan 50 mg. - Genetic Profile P2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

10.7

Confidence interval

level

95%

sides

2-sided

lower limit

2.75

upper limit

18.72

Other pre-specified: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2 unadjusted

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End point title

Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 6 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Caucasian subjects carrying at least one pair of gene variants included in the genetic profile P2, mean change.

End point values	Caucasian rostafuroxin 6 microg. - Genetic Profile P2	Caucasian losartan 50 mg. - Genetic Profile P2
Number of subjects analysed	20	23
Units: mmHg
arithmetic mean (confidence interval 95%)	-8.7 (-15.33 to -2.13)	-13.1 (-19.27 to -6.96)

P2 - rostafuroxin 6 microg. vs losartan- Caucasian

Statistical analysis description

ANOVA/ Caucasian - 6 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 6 microg. - Genetic Profile P2 v Caucasian losartan 50 mg. - Genetic Profile P2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.336

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

4.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.64

upper limit

13.4

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2 unadjusted

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End point title

Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 50 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Caucasian subjects carrying at least one pair of gene variants included in the genetic profile P2, mean change.

End point values	Caucasian rostafuroxin 50 microg. - Genetic Profile P2	Caucasian losartan 50 mg. - Genetic Profile P2
Number of subjects analysed	17	23
Units: mmHg
arithmetic mean (confidence interval 95%)	-22.2 (-29.39 to -15.08)	-13.1 (-19.27 to -6.96)

P2 - rostafuroxin 50 microg. vs losartan-Caucasian

Statistical analysis description

ANOVA/ Caucasian - 50 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 50 microg. - Genetic Profile P2 v Caucasian losartan 50 mg. - Genetic Profile P2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.058

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

-9.1

Confidence interval

level

95%

sides

2-sided

lower limit

-18.56

upper limit

0.31

Other pre-specified: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2 unadjusted

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End point title

Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P2. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 500 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Caucasian subjects carrying at least one pair of gene variants included in the genetic profile P2, mean change.

End point values	Caucasian rostafuroxin 500 microg. - Genetic Profile P2	Caucasian losartan 50 mg. - Genetic Profile P2
Number of subjects analysed	19	23
Units: mmHg
arithmetic mean (confidence interval 95%)	-19.7 (-26.48 to -12.95)	-13.1 (-19.27 to -6.96)

P2 -rostafuroxin 500 microg. vs losartan-Caucasian

Statistical analysis description

ANOVA/ Caucasian - 500 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian losartan 50 mg. - Genetic Profile P2 v Caucasian rostafuroxin 500 microg. - Genetic Profile P2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.155

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

-6.6

Confidence interval

level

95%

sides

2-sided

lower limit

-15.75

upper limit

2.54

Other pre-specified: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P1 unadjusted

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End point title

Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P1 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P1. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 6 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Caucasian subjects carrying at least one gene variant or one pair of gene variants included in the genetic profile P1, mean change.

End point values	Caucasian rostafuroxin 6 microg. - Genetic Profile P1	Caucasian losartan 50 mg. - Genetic Profile P1
Number of subjects analysed	36	40
Units: mmHg
arithmetic mean (confidence interval 95%)	-5.8 (-10.78 to -0.91)	-17.5 (-22.14 to -12.77)

P1 - rostafuroxin 6 microg. vs losartan -Caucasian

Statistical analysis description

ANOVA/ Caucasian - 6 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian losartan 50 mg. - Genetic Profile P1 v Caucasian rostafuroxin 6 microg. - Genetic Profile P1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

11.6

Confidence interval

level

95%

sides

2-sided

lower limit

4.81

upper limit

18.41

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P1 unadjusted

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End point title

Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P1 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P1. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 50 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Caucasian subjects carrying at least one gene variant or one pair of gene variants included in the genetic profile P1, mean change.

End point values	Caucasian rostafuroxin 50 microg. - Genetic Profile P1	Caucasian losartan 50 mg. - Genetic Profile P1
Number of subjects analysed	35	40
Units: mmHg
arithmetic mean (confidence interval 95%)	-17.3 (-22.31 to -12.30)	-17.5 (-22.14 to -12.77)

P1 - rostafuroxin 50 microg. vs losartan-Caucasian

Statistical analysis description

ANOVA/ Caucasian - 50 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 50 microg. - Genetic Profile P1 v Caucasian losartan 50 mg. - Genetic Profile P1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.965

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-6.7

upper limit

7.01

Other pre-specified: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P1 unadjusted

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End point title

Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P1 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P1. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 500 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Caucasian subjects carrying at least one gene variant or one pair of gene variants included in the genetic profile P1, mean change.

End point values	Caucasian rostafuroxin 500 microg. - Genetic Profile P1	Caucasian losartan 50 mg. - Genetic Profile P1
Number of subjects analysed	39	40
Units: mmHg
arithmetic mean (confidence interval 95%)	-16.0 (-20.74 to -11.26)	-17.5 (-22.14 to -12.77)

P1 -rostafuroxin 500 microg. vs losartan-Caucasian

Statistical analysis description

ANOVA/ Caucasian - 500 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Caucasian rostafuroxin 500 microg. - Genetic Profile P1 v Caucasian losartan 50 mg. - Genetic Profile P1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.667

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

1.46

Confidence interval

level

95%

sides

2-sided

lower limit

-5.21

upper limit

8.12

Other pre-specified: Chinese OSBP difference between 50 mcg rostafuroxin and Losartan - P1 unadjusted

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End point title

Chinese OSBP difference between 50 mcg rostafuroxin and Losartan - P1 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P1. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 50 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Chinese subjects carrying at least one gene variant or one pair of gene variants included in the genetic profile P1, mean change.

End point values	Chinese rostafuroxin 50 microg. - Genetic Profile P1	Chinese losartan 50 mg. - Genetic Profile P1
Number of subjects analysed	30	33
Units: mmHg
arithmetic mean (confidence interval 95%)	-2.7 (-6.69 to 1.23)	-15.9 (-19.72 to -12.17)

P1 - rostafuroxin 50 microg. vs losartan - Chinese

Statistical analysis description

ANOVA/ Chinese - 50 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Chinese rostafuroxin 50 microg. - Genetic Profile P1 v Chinese losartan 50 mg. - Genetic Profile P1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

13.2

Confidence interval

level

95%

sides

2-sided

lower limit

7.74

upper limit

18.68

Other pre-specified: Chinese OSBP difference between 500 mcg rostafuroxin and Losartan - P1 unadjusted

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End point title

Chinese OSBP difference between 500 mcg rostafuroxin and Losartan - P1 unadjusted

End point description

The change in the office systolic blood pressure (OSBP) over 2 months was measured in carriers of the genetic profile P1. The between group comparison was performed on the change from baseline to treatment of OSBP using an analysis of variance (ANOVA) model. Analysis compared the group treated with 500 mcg rostafuroxin versus the group treated with losartan.

End point type

Other pre-specified

End point timeframe

Office Systolic Blood pressure (OSBP) change two month-treatment - Chinese subjects carrying at least one gene variant or one pair of gene variants included in the genetic profile P1, mean change.

End point values	Chinese rostafuroxin 500 microg. - Genetic Profile P1	Chinese losartan 50 mg. - Genetic Profile P1
Number of subjects analysed	33	33
Units: mmHg
arithmetic mean (confidence interval 95%)	-4.6 (-8.37 to -0.82)	-15.9 (-19.72 to -12.17)

P1 - rostafuroxin 500 microg. vs losartan -Chinese

Statistical analysis description

ANOVA/ Chinese - 500 microg. rostafuroxin vs. losartan, Per Protocol Set ANOVA model with change from baseline to visit 6 as dependent variable, treatment as fixed effect.

Comparison groups

Chinese rostafuroxin 500 microg. - Genetic Profile P1 v Chinese losartan 50 mg. - Genetic Profile P1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

11.4

Confidence interval

level

95%

sides

2-sided

lower limit

6.01

upper limit

16.69

Adverse events

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Timeframe for reporting adverse events

Double-blind, 9 week-period for each patient. June 26, 2013 - March 28, 2016 for Caucasian December 18, 2015 - February 8, 2018 for Chinese

Adverse event reporting additional description

Patients were monitored throughout the study for AEs which were documented and collected on an ongoing basis during the treatment period and the relevant follow up period. In addition, patients were instructed to record any AEs in the Patient Diary.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.1

Reporting group title

6 microg. rostafuroxin Caucasian

Reporting group description

Reporting group title

50 microg. rostafuroxin Caucasian

Reporting group description

Reporting group title

500 microg. rostafuroxin Caucasian

Reporting group description

Reporting group title

50 mg. losartan Caucasian

Reporting group description

Reporting group title

50 microg. rostafuroxin Chinese

Reporting group description

Reporting group title

500 microg. rostafuroxin Chinese

Reporting group description

Reporting group title

50 mg. losartan Chinese

Reporting group description

Serious adverse events	6 microg. rostafuroxin Caucasian	50 microg. rostafuroxin Caucasian	500 microg. rostafuroxin Caucasian	50 mg. losartan Caucasian	50 microg. rostafuroxin Chinese	500 microg. rostafuroxin Chinese	50 mg. losartan Chinese
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 4%

Non-serious adverse events	6 microg. rostafuroxin Caucasian	50 microg. rostafuroxin Caucasian	500 microg. rostafuroxin Caucasian	50 mg. losartan Caucasian	50 microg. rostafuroxin Chinese	500 microg. rostafuroxin Chinese	50 mg. losartan Chinese
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 42 (11.90%)	5 / 42 (11.90%)	7 / 43 (16.28%)	8 / 43 (18.60%)	17 / 35 (48.57%)	21 / 34 (61.76%)	20 / 35 (57.14%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Monoclonal gammopathy
subjects affected / exposed	1 / 42 (2.38%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Gastrointestinal submucosal tumour
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Neoplasm
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	2 / 35 (5.71%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Surgical and medical procedures
Tooth extraction
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 42 (2.38%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	0	0	0	0	1
Malaise
subjects affected / exposed	1 / 42 (2.38%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Chest discomfort
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	0	0	2
Reproductive system and breast disorders
Female sexual dysfunction
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Menstruation irregular
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 42 (2.38%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Dyspnoea
subjects affected / exposed	0 / 42 (0.00%)	1 / 42 (2.38%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 42 (0.00%)	1 / 42 (2.38%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	1	0	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Nasal septum deviation
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Psychiatric disorders
Anxiety disorder
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	1	0	1
Insomnia
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	8	1	0
Anxiety
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Investigations
Blood pressure abnormal
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Lymphocyte percentage decreased
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Neutrophil count increased
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Transaminases increased
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 42 (0.00%)	1 / 42 (2.38%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	1	0	0	0	0	1
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	2 / 35 (5.71%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	2	1	1
Left ventricular hypertrophy
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	1	0	1
Nervous system disorders
Headache
subjects affected / exposed	2 / 42 (4.76%)	3 / 42 (7.14%)	2 / 43 (4.65%)	4 / 43 (9.30%)	2 / 35 (5.71%)	4 / 34 (11.76%)	1 / 35 (2.86%)
occurrences all number	2	10	2	10	2	9	1
Dizziness
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	2 / 35 (5.71%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	0	0	1	2	2	1
Tremor
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	0	0	4
Loss of consciousness
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Tension headache
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	2	0	0
VIth nerve paralysis
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Tinnitus
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Gastrointestinal disorders
Dyspepsia
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	1	1	0	2
Gastritis
subjects affected / exposed	0 / 42 (0.00%)	1 / 42 (2.38%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	1	0	0	0	0	1
Diarrhoea
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	2 / 35 (5.71%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	2	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	2	1
Abdominal distension
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	0	0	2
Gastrointestinal hypermotility
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Gingival bleeding
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	2
Haemorrhoids
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Irritable bowel syndrome
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Mouth ulceration
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Peptic ulcer
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	0	1	2
Hepatic steatosis
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	1 / 42 (2.38%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Rash
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Erythema
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	3	0
Pruritus
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Pustular psoriasis
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Skin exfoliation
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Proteinuria
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 42 (4.76%)	1 / 42 (2.38%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	1	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Pain in extremity
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	0	0	1	0	0	1	2
Arthralgia
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Neck pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Patellofemoral pain syndrome
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Tendonitis
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	1	1	0	0	1
Bronchitis
subjects affected / exposed	1 / 42 (2.38%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Influenza
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Nasopharyngitis
subjects affected / exposed	1 / 42 (2.38%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	5 / 35 (14.29%)	3 / 34 (8.82%)	3 / 35 (8.57%)
occurrences all number	1	0	0	0	5	3	3
Rhinitis
subjects affected / exposed	0 / 42 (0.00%)	1 / 42 (2.38%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	1	0	0
Tooth abscess
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	2 / 34 (5.88%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	1	2	2
Gastroenteritis viral
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Metabolism and nutrition disorders
Gout
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	2 / 35 (5.71%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	3	0	1
Hyperlipidaemia
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	1	1	1
Hyperglycaemia
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hypercalcaemia
subjects affected / exposed	0 / 42 (0.00%)	0 / 42 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

25 Oct 2012

Amendment N.1

27 Mar 2013

Amendment CVT-CV-001 IT3

30 Jan 2014

Amendment CVT CV-001 IT6

27 May 2014

Amendment CVT CV-001 IT6 v.2

25 Jun 2015

Amendment N.2.1

11 Jul 2017

Amendment N.3 V.1

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
21 Nov 2013	PEARL-HT was interrupted in November 2013 because of the discovery of the mold in the 50 microgr. batch. The appropriate action was taken and approved by AIFA, and the clinical trial restarted in October 2014.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Antihypertensive effect of different doses of ROSTAFUROXIN in comparison with Losartan, assessed by office and ambulatory blood pressure monitoring in a hypertensive population selected according to a specific genetic profile.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2a adjusted

Primary: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2a adjusted

Primary: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2a adjusted

Primary: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2a adjusted

Primary: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2a adjusted

Primary: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2a adjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS AA adjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS AA adjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS CC adjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS CC adjusted

Other pre-specified: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2 adjusted

Other pre-specified: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2 adjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2 adjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2 adjusted

Other pre-specified: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2 adjusted

Other pre-specified: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2 adjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS AA/CC adjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - LSS AA/CC adjusted

Other pre-specified: Chinese OSBP difference between 50 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Chinese OSBP difference between 50 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Chinese OSBP difference between 500 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Chinese OSBP difference between 500 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P2 unadjusted

Other pre-specified: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P1 unadjusted

Other pre-specified: Caucasian OSBP difference between 6 mcg rostafuroxin and Losartan - P1 unadjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P1 unadjusted

Other pre-specified: Caucasian OSBP difference between 50 mcg rostafuroxin and Losartan - P1 unadjusted

Other pre-specified: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P1 unadjusted

Other pre-specified: Caucasian OSBP difference between 500 mcg rostafuroxin and Losartan - P1 unadjusted

Other pre-specified: Chinese OSBP difference between 50 mcg rostafuroxin and Losartan - P1 unadjusted

Other pre-specified: Chinese OSBP difference between 50 mcg rostafuroxin and Losartan - P1 unadjusted

Other pre-specified: Chinese OSBP difference between 500 mcg rostafuroxin and Losartan - P1 unadjusted

Other pre-specified: Chinese OSBP difference between 500 mcg rostafuroxin and Losartan - P1 unadjusted

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Antihypertensive effect of different doses of ROSTAFUROXIN in comparison with Losartan, assessed by office and ambulatory blood pressure monitoring in a hypertensive population selected according to a specific genetic profile.