Clinical Trials Register

Summary
EudraCT Number:	2020-004971-42
Sponsor's Protocol Code Number:	RVT-1201-2002
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-05-06
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

Czechia - SUKL

A.2

EudraCT number

2020-004971-42

A.3

Full title of the trial

A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Rodatristat Ethyl in Patients with Pulmonary Arterial Hypertension

Randomizovaná, dvojitě-zaslepená, placebem kontrolovaná multicentrická studie fáze 2b hodnotící použití různých dávek rodatristat ethylu u pacientů s plicní arteriální hypertenzí

A.3.1

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

A Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension (ELEVATE 2)

A.3.2

Name or abbreviated title of the trial where available

ELEVATE 2

A.4.1

Sponsor's protocol code number

RVT-1201-2002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04712669

A.5.4

Other Identifiers

Name:

IND

Number:

126945

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	Altavant Sciences GmbH
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Altavant Sciences GmbH
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Altavant Sciences GmbH
B.5.2	Functional name of contact point	Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Viaduktstrasse 8
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4051
B.5.3.4	Country	Switzerland
B.5.6	E-mail	clinicaltrials@altavant.com

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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/17/1861
D.3 Description of the IMP
D.3.1	Product name	Rodatristat ethyl
D.3.2	Product code	RVT-1201
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	Rodatristat ethyl
D.3.9.1	CAS number	1673571-51-1
D.3.9.2	Current sponsor code	RVT-1201
D.3.9.3	Other descriptive name	Rodatristat ethyl
D.3.9.4	EV Substance Code	SUB198073
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	300
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pulmonary Arterial Hypertension (PAH)

E.1.1.1

Medical condition in easily understood language

Pulmonary Arterial Hypertension (PAH) is a serious and rare disease of increased blood pressure within the arteries of the lungs.

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10037400
E.1.2	Term	Pulmonary hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the effect of rodatristat ethyl on the percent change from baseline of pulmonary vascular resistance (PVR), as measured by right heart catheterization (RHC) in patients with PAH.

E.2.2

Secondary objectives of the trial

• To evaluate the effect of rodatristat ethyl from baseline to Week 24 on:
o WHO FC
o 6MWD
o N-terminal pro-Brain Natriuretic Peptide (NT-proBNP)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients are eligible to be included in the study only if all the following criteria are met:
1. Male and female patients must be at least 18 years of age at the time of signing the informed consent.
a. Male patients and female partners of childbearing potential must agree to use contraception as detailed in a Section 5.4.1 to the protocol starting at screening, during the treatment period, and for at least 100 days after the last dose of IP. Male patients must refrain from donating sperm during this period.
b. Female patients of childbearing potential must agree to use contraception as detailed in Section 5.4.1 starting at Screening, during the treatment period, and for at least 4 weeks after the last dose of IP.
2. Body mass index (BMI) ≥ 18 kg/m2 and ≤ 40 kg/m2
3. Patients with symptomatic PAH belonging to one of the following 2018 Clinical Group 1 sub types:
a. Idiopathic PAH
b. Heritable PAH
c. Drug or toxin induced
d. PAH associated with:
1. Connective tissue disease
2. Congenital systemic to pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) repaired at least one year prior to Screening
3. Human immunodeficiency virus (HIV) infection - if diagnosed with HIV, must have stable disease status defined as follows:
a. stable treatment with HIV medications for at least 8 weeks prior to Screening
b. no active opportunistic infection during the Screening Period
c. no hospitalizations due to HIV for at least 4 weeks prior to Screening
4. WHO FC II or III
5. Confirmed diagnosis of PAH and meet all the following hemodynamic criteria by means of a screening RHC completed prior to randomization:
a. mPAP of ≥ 20 mmHg
b. PVR ≥ 350 dyne•sec/cm5
c. Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of ≤ 12 mmHg if PVR ≥ 350 and < 500 dyne•sec/cm5, or PCWP/LVEDP ≤ 15 mmHg if PVR ≥ 500 dyne•sec/cm5
6. 6MWD of 100 to 550 meters at Screening
7. Currently on a stable treatment regimen with one or more treatments approved for PAH. Stable therapy is defined as receiving the same medication(s) for ≥ 12 weeks prior to the screening RHC and at a stable dose level for each for ≥ 8 weeks prior to the screening RHC. Any instances where doses of a medication have been missed prior to RHC must be discussed with the Medical Monitor prior to performing the RHC.
8. Meet all of the following criteria determined by pulmonary function tests completed no more than 24 weeks prior to Screening (performed with or without bronchodilation):
a. Forced expiratory volume in one second (FEV1) ≥ 60% of predicted normal, and
b. Total lung capacity (TLC) ≥ 70% of predicted normal or FVC ≥ 70% predicted if TLC is not available; For subjects with CTD associated PAH, if TLC is ≥ 60% of predicted but < 70% of predicted of if FVC ≥ 60% or predicted but < 70% of predicted, high resolution computed tomography [HRCT] obtained within 6 months of screening may be utilized to demonstrate limited interstitial lung disease
9. If participating in an exercise program for pulmonary rehabilitation, the program must have been initiated ≥ 12 weeks prior to Screening, and patient must agree to maintain the current level of rehabilitation for the first 24 weeks of receiving IP. If not participating in an exercise training program for pulmonary rehabilitation, patient must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 24 weeks of receiving IP.
10. Willing and able to give written informed consent and to comply with the requirements of the study for its duration

E.4

Principal exclusion criteria

1. Women of childbearing potential who are pregnant, planning to become pregnant, or lactating or female/male patients unwilling to use effective contraception as defined in Section 5.4.1
2. WHO pulmonary hypertension (PH) Group 1 PAH associated with portal hypertension or schistosomiasis; PH due to left heart disease (WHO PH Group 2), lung diseases and/or hypoxia (WHO PH Group 3), chronic thromboembolic PH (WHO PH Group 4), or PH with unclear multifactorial mechanisms (WHO PH Group 5)
3. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), pulmonary capillary hemangiomatosis, portal hypertension, or unrepaired congenital heart defects (CHD)
4. Three or more of the following risk factors for left ventricular disease:
a. BMI ≥ 30 kg/m2
b. Diagnosis of essential hypertension that is actively treated
c. Diabetes mellitus
d. History of significant coronary artery disease (e.g., chronic stable angina, history of coronary intervention within the last 3 months, or a stenosis > 70% at coronary angiography)
e. Atrial fibrillation
f. Left atrial volume index > 41 mL/m2 [or left atrial diameter (LA) > 4 cm if LAVI unavailable]
5. Known genetic hypertrophic cardiomyopathy
6. Known cardiac sarcoidosis or amyloidosis
7. The patient has a history of, or currently has, a constrictive cardiomyopathy
8. Known history of any left ventricular ejection fraction (LVEF) < 40% by echocardiogram within 3 years of randomization (Note: a transient decline in LVEF below 40% that occurred and recovered more than 6 months before the start of Screening and was associated with an acute intercurrent condition [e.g., atrial fibrillation] is allowed)
9. Hemodynamically significant valvular heart disease as determined by the Investigator, including:
a. greater than mild aortic and/or mitral stenosis and/or
b. severe mitral and/or aortic regurgitation (> Grade 3)
10. Severe arthritis, musculoskeletal problems, or morbid obesity that, in the opinion of the Investigator, is the cause of the patient’s functional limitation and would affect the patient’s ability to perform or complete the 6MWT
11. Planned major surgery within the next 3 months, including lung transplantation, major abdominal or major intestinal surgery
12. End stage renal disease defined as receiving peritoneal dialysis, hemodialysis, or status after renal transplantation, or severe liver disease defined as Child Pugh Class C, with or without cirrhosis
13. Known congenital LQTS or known family history of LQTS
14. Depression that is currently rated as severe (defined as a score of ≥ 16 on the QIDS C and/or [HADS] Depression and/or Anxiety score ≥ 15), recent suicidal behavior (either preparatory acts/behavior, aborted attempt, interrupted attempt, or actual attempt in the past 3 months per the Screening C SSRS), or active suicidal ideation with intent to act (defined as C SSRS category score of 4 or 5 in the past month)
15. Patients with (during Screening):
a. Severe hypertension (SBP > 180 mmHg and/or Diastolic Blood Pressure [DBP] > 110 mmHg), and patients with severe hypotension (SBP < 90 mmHg and/or DBP < 50 mmHg)
b. Hypertension or hypotension considered not controlled in line with clinical standards.

Other exclusion criteria apply per study protocol.

E.5 End points

E.5.1

Primary end point(s)

Percent change from baseline to 24 weeks of pulmonary vascular resistance (PVR) between an active arm and the placebo arm.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 24

E.5.2

Secondary end point(s)

• Change from baseline in WHO FC
• Change from baseline in 6MWD
• Change from baseline in NT proBNP

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 24

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

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

Canada

United States

Bosnia and Herzegovina

Moldova, Republic of

Ukraine

Serbia

Austria

Belgium

Bulgaria

Czechia

France

Germany

Italy

Latvia

Poland

Spain

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients in the Main Study that do not discontinue prematurely and complete up to and including the Week 24 Visit, have the option to rollover into the Open Label Extension (OLE).

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

2021-07-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-22

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-08-28

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