SELEXIPAG / ACT-293987

Pulmonary Arterial Hypertension

Protocol AC- 065A303
GRIPHON OL
 
All subjects still being treated with selexipag in Study AC-065A303 (GRIPHON OL) will re-sign
consent at the next study visit (scheduled or unscheduled) after the center is informed of full
approval of the modified subject information booklet and consent form by all local authorities
(health authority, institutional ethics committee, institutional review board, etc.)

Informative Brochure for the Subject

AC- 065A303
GRIPHON: Prostacyclin (P G I  ) R eceptor agonist I n P ulmonary arterial H ypertensi ON ( pros
2 

tacyclin receptor agonist [PGI2] in pulmonary arterial hypertension)

Study open, long term, of one branch to evaluate the safety and tolerability
of Selexipag (ACT-293987) in patients with pulmonary arterial hypertension.
 
Researcher P ain / Institution S avalanche : <insert names, addresses, contact numbers of staff of
the study (eg researcher, the study nurse.) Responsible for the care of the subjects included>
 
 
Sponsor: Actelion Pharmaceuticals Ltd., Allschwil , Switzerland
 
Name l Patient: __________________________________________
 
INTRODUCTION
 
Dear (a) patient,
 
You have been invited to participate in this clinical research study because you have pulmonary
arterial hypertension ( PAH ) and have participated in Study AC-065 A 302 (GRIPHON) . This
study, AC-065 A 303 (GRIPHON OL), is an open-label study, which means that if you decide to
participate, you will receive the active study drug selexipag (you already knew it under the
code ACT-293987 ) . An investigational drug is one that is under consideration for approval by the
Food and Drug Administration US ( FDA) and other regulators, agencies such as
the Directorate General of Medicines , Supplies and Drugs ( DIGEMID) in Peru .
 
In order to decide whether or not to participate in this study, please read the following information
carefully. This consent form contains new information in addition to that submitted on the form
you previously received. Before you give your agree to continue in the study, you need to
understand what has changed and how these changes may affect you. You must be sure
you understand the potential benefits and risks to make an informed decision. If after
reading this Subject Information Leaflet / Informed Consent Form , there is something you do
not understand about this study or the drug , consult your study physician .
 
All changes to the original informed consent that you previously signed are underlined.
 
  Based on new information on how other medications may affect the study drug
( selexipag ), you are advised that your doctor may change your dose of  selexipag if you must
start taking certain medications.
 For clarity, the potential side effects of  selexipag are listed by frequency.
 You are informed that your hospital or research center will keep your records for 10 years
according to the regulations .
 
This study has been approved by the Independent Ethics Committee (IEC ) of your clinic /
institution . Their contact details are at the end of this form . It will be carried out in accordance
with the regulations governing clinical research.
 
An Independent Ethics Committee (IEC) is an independent body ( a review board or an
institutional, regional, national or supranational committee), made up of medical professionals and
non-medical members, whose responsibility is to ensure the protection of rights, safety and welfare
of human subjects involved in a trial and to provide public assurance of the respect, through,
interlnal, review and approval / favorable opinion on the protocol of the test the suitability
of the researchers, facilities and methods and materials that will be used to obtain and document the
informed consent of the trial subjects.
 
INFORMATION ABOUT THE DISEASE AND THE COMPOUND 
 
Pulmonary arterial hypertension is an uncommon disease that can occur on its own, or it may be
related to other causes. It is a serious medical condition and should be treated as soon as possible.
 
PAH occurs when the blood pressure in the pulmonary arteries, the vessels that carry blood from
the heart to the lungs to pick up oxygen, rises above normal levels. Blood consecuently has more
and more difficulty flowing through the pulmonary vessels, and your heart works less and less
efficiently.
 
Selexipag is the same drug used in the GRIPHON study. Selexipag works in a similar way to a
substance natural in the body called prostacyclin . Prostacyclin production is decreased in patients
with PAH. Selexipag can lower blood pressure in the lungs and improve exercise capacity in
patients with PAH.
 
This drug has  not been approved by the General Directorate
of Medicines , Supplies and Drugs ( DIGEMID) in Peru .
 
THE PURPOSE OF THE STUDY
 
The main objective of this clinical research study is to assess how well PAH patients can tolerate
the drug after taking selexipag for a long period, and to collect information on any side effects or
illnesses that may occur.
 
PARTICIPANTS
 
Patients participating in the study GRIPHON who have completed treatment extension l GRIPHON
study, and patients who experienced a deterioration of their HAP during GRIPHON study.
 
It will include about 1,150 patients with pulmonary arterial hypertension about 161 research centers
in 39 countries worldwide. In Peru, approximately 1 5 patients will be recruited .
 
STUDY DURATION
 
You will be able to stay in Study AC-065A303 / GRIPHON OL until one of the following occurs:
 
 the Selexipag is available for marketing to treat PAH in their country ; or
 the sponsor decides to stop the study; or
 you or your doctor decide to stop the study medication.
 
TREATMENT (S) OF THE STUDY
 
In this study, patients will receive active selexipag .
 
The medication study you receive comes in the form of tablets , and asks you to
take l as tablets orally ( by mouth) twice a day , once in the morning and one at night ,
preferably with meals.
 
Due to the way this study medication works , not all patients will need the same number
of tablets . The number of tablets to take depends on how well that pued to tolerate the drug, and
can vary from one tablet and a maximum of 8 tablets twice a day. The dose ( number
of tablets ) of the study medication should be increased slowly so that you can better tolerate it .
 
If you join the study GRIPHON OL after completing the period of extension of the
treatment of GRIPHON, your doctor will know what treatment was before. If you
received selexipag in the GRIPHON study, you will continue on the same dose.
 
If you received placebo in the GRIPHON study or if you entered the GRIPHON OL study
after experiencing a worsening of your disease in the GRIPHON study , you will start
taking selexipag in the GRIPHON OL study at the lowest dose .
 
E n this case, and mpezará to take one tablet twice a day. After a week, your doctor will tell you to
start taking 2 tablets twice a day . Each week the dose will be increased by 1 tablet twice a day until
you reach the highest possible dose that you can tolerate well. Your doctor will discuss this with
you and decide what dose to keep. The dose of the study drug may be lowered or stopped during the
study, depending on your doctor's decision in case you experience any side effects.
 
 
 
 
STUDY PROCEDURES
 
During the first visit (Visit 1) , the doctor will explain the study to you in detail . If you are
interested in participating , you will be asked to read this document and to sign the informed
consent form before starting any procedure or test that is required for the study.
 
- If you were already receiving selexipag treatment in the GRIPHON study:
 
Without interruption, you will continue taking the same dose of the drug in the study as it did in the
GRIPHON study, and will come to the center every 6 I s is (Visit 1, Visit 5, Visit 6, etc.) to visit the
End of the Study . After 12 weeks, and between one visit and another semester (beginning with the
month 9), your doctor will call you by phone to ask about your general health.
 
- If you received place b o in the GRIPHON study or if you  entered the GRIPHON OL study after
experiencing a worsening of your disease during the GRIPHON study:
 
On the afternoon of the Visit 1 , you start taking the study medication at the lowest dose of 1 tablet
twice a day, and increase to the dose of one tablet twice a day every week. For this, you will have to
come to l a clinic / hospital to visit 2 (after 4 weeks), to Visit 3 (after 8 weeks) and Visit 4 (after 16
weeks). Each week between Visit 1 and Visit 2, and between the s Visit 2 and 3, and after 12
weeks , your doctor will call to ask about your general health. He / she will tell you to c or mo
increase the dose (number of tablets) of the study medication, and will be asked to note the number
of tablets in patient card.
 
From Visit 5 onwards (ie after 6 months), you should come to l a clinic / hospital every 6 months
and between visits every six months and another (from month 9) your doctor will phone to ask
about your general health.
 
At each visit , your doctor will ask you some questions about your general health and the medicines
you take. It is important that you have discussed all alternative treatments for your PAH with your
doctor before participating in this study. You should also know that it will not be necessary to make
any changes to your current PAH therapy. This means that you will continue to take the medicines
your doctor has prescribed to treat your HAP, and that you will receive selexipag in addition to your
current therapy. The only medicines against HAP which are not permitted during the course of this
study are analogs oral of the prostacyclin (such as treprostinil or beraprost ). This is
because the mode of action of these therapies is very similar to selexipag , the investigational drug
in this study. You should inform your doctor before starting a new therapy for HAP. Throughout
the course of this study, your doctor will discuss with you regularly, during clinic visits, if there is
any new treatment for HAP available.
 
At each visit, your doctor will do a physical exam, measure your blood pressure, heart rate, and
weight. He / she will draw a small amount of blood from your arm (about two
teaspoons), for routine lab tests. If you are a woman who can have children , you will be asked
to take a pregnancy test every month for up to a month after you have stopped taking the study
drug . This can be done during your visit to l a clinic / hospital in a local laboratory , or in
your home test kit urine pregnancy your doctor will provide during each visit. You will have
to complete the card pregnancy test after each monthly test , and llevarl to your next visit
to l a clinic / hospital .
 
On each visit , you must bring all the tablets remaining and all containers ( even if they were
empty).
 
End visit of the E studio
Either when the sponsor notify your clinic / hospital that the study is over, or if your doctor
or you decide you want to stop taking the drug for l study , you will be asked to come to visit End of
the Study. During this visit, they will perform the same assessments that the visits earlier . This
visit also must return tod as their tablets remaining and all containers of l drug ( even if they
were empty ).
 
Follow - up to 30 days
Your doctor will contact you by phone 30 days after your last dose of drug in the study , to collect
information about the possible effects side or diseases that may have occurred during this time.
 
RISKS AND DISCOMFORTS
 
The investigational drug and testing procedures have risks and hassles . As in any clinical research
study , this drug under investigation may have effects undesirable and may also cause
some problems still not known. However , your doctor will follow closely and will monitor the
effects unwanted or any problems .
 
The risk that can run during specific tests of the study is a slight risk of pain , bruising and infection
when blood is drawn from your arm to test clinical blood tests .
 
A very common side effect reported to date with selexipag in the GRIPHON
study is headaches (65% of patients, 2 out of 3 patients) . One can also observe one or more of the
following effects side :
Very common side effects (may affect more than 1 in 10 people)
- headache         
- Redness of the face         
- Nausea and vomiting         
- diarrhea         
- Jaw pain, muscle pain, joint pain, leg pain         
- Nasopharyngitis (nasal congestion and sore throat)         
 
Common side effects (which may affect up to 1 in 10 people)
- Anemia (low levels of red blood cells)         
- Hyperthyroidism (extremely active thyroid gland         
- Decreased appetite         
- Weight loss         
- Hypotension (low blood pressure)         
- Stomach pain         
- pain         
- Skin rashes, including hives, can cause a burning or stinging sensation and redness of the
skin         
 
Uncommon side effects (may affect up to 1 in 100 people)
- Increased heart rate         
 
Some cases of hyperthyroidism (an extremely active thyroid gland) have been seen
with selexipag treatment . Your doctor may decide if additional tests are needed to evaluate your
thyroid function.
 
A study carried out in mouse
cells first shows that selexipag can cause phototoxic reactions (sensitivity to sunlight ). However,
a study in healthy volunteers did not indicate that selexipag causes phototoxic reactions in humans .
 
In a study in dogs with very high doses of Selexipag ( more alt as what will be provided to you) ,
they were observed cases of intussusception ( this means that sections of the intestine is Slipper za n
in other sections as much as the pieces of a telescope ) . This condition increases the risk
of a bowel obstruction and requires medical intervention . Changes in the structure of the
bones were also observed leading to a hardening of the bone. Animal studies in rats and dogs also
showed an inhibition of platelet aggregation ( interference with the blood clots ) this could lead
to an increased risk of bleeding . In the GRIPHON study, none of these findings were confirmed
in PAH patients receiving selexipag .
 
In a two-year study in rats, changes in the shape of blood vessels in the back of the eye (called
retinal blood vessel tortuosity) have been observed with high doses of selexipag (10 mg / kg / day
and above. ). These changes in the shape of the blood vessels were not associated with any
indication of damage to the tissues at the back of the eye. These changes were only seen in
rats, they were not seen in patients taking selexipag in the GRIPHON study .
 
If adverse note effects or signs of allergic reaction (eg , swelling of the face or tongue ,
rash, pic Azón ) while you are taking your medication study , or if any of the effects side mentioned
above is concerned, see your doctor .
 
They may arise other complications and side effects of Selexipag , which are not yet known at this
time . You will be informed of new findings related to the safety of the drug , and you will
receive any new information that becomes available during the study that could change
your willingness to continue participating in the study.
 
Please inform your doctor if you intend to start taking a new medication, and about any medications
you are taking or have recently taken . This includes medicines that you have bought without
a prescription, as some of them could interact with selexipag . Recent new results have shown
that some medications can influence how much selexipag is released into your body. This can
increase unwanted side effects. If you need to start taking medicines such as rifampicin , an
antibiotic, the dose of selexipag you are taking may need to be changed. Other drugs, such as the
lipid-regulating drug gemfibrozil , should not be taken with selexipag . Therefore, before taking any
new medications during the study, you should consult with your study doctor.
 
If you feel dizzy while taking selexipag , please do not drive or use tools or machines .
 
PREGNANCY
 
You cannot take part in this study if you are pregnant or breastfeeding.
 
No known security Selexipag during pregnancy , and there is no information available about
whether the study drug is harmful for embryos / fetuses human .
 
If you are a woman who can have children , you must use a form with reliable birth control during
the study , and for 1 month after stopping the study medication .
 
In the study GRIPHON OL , the reliable forms of birth control are defined as one of the following:
 
 a permanent method of contraception (for
example , bilateral tubal ligation , or transcervical sterilization for you or vasectomy for your
partner ) ;
 one of the following contraception : devices intrauterine , contraceptive agents oral or
injectable , ring vaginal hormonal implants hormonal , patches contraceptive hormonal skin .
 barrier methods in combination with a spermicide ( for example, female condoms , the
diaphragm, contraceptive sponge , or male condom )
 
Please note that the rhythm method is NOT an acceptable method of contraception for the purposes
of this study.
 
Both the Sponsor and the Investigator will ensure that the subject has access to an effective method
of birth control at no cost. Both men and women should agree to use an efficient method of birth
control. Throughout the course of the study, you and your partner must agree to use a medically
acceptable contraceptive, for example condoms or birth control pills. The sponsor has agreed to
cover the reasonable cost of an effective contraceptive method and will provide the contraceptives
to you while you are in the study.
 
If you are naturally amenorrheic (no t iene your period menstrual) you take one confirmation of
their condition by a gynecologist to be able to participate in the study without using a reliable form
of birth control .
 
If you have been postmenopausal ( no longer have your period ) for at the least 2 years can
participate in the study without being tested s pregnancy.
 
If you are a woman who is capable of having children , a pregnancy test will be carried out prior
to inclusion in the study , and pregnancy tests will also be carried out every month during the study
and 1 month after stopping taking study medication . If you suspect that you are pregnant ,
you should inform your doctor immediately .
 
If you become pregnant during the study , you will be withdrawn from the study and your doctor
will follow the course of your pregnancy , and after the birth until the baby is six months old .
 
BENEFITS
 
Patients who took selexipag in the GRIPHON study have been shown to have a significant delay in
disease progression (e.g. hospitalization, impaired walking distance, need for new PAH therapies)
compared to patients who received placebo . The information obtained in the course
of this clinical research study can contribute to a better understanding of your disease , and may be
helpful in selecting medications for your treatment in the future . Regardless of
any individual benefits , the knowledge gained from this study may
contribute to obtaining information that will allow the use of this
medicine for future treatment for you and other patients with PAH.
 
ALTERNATIVES TO PARTICIPATION
 
If you do not wish to participate in this clinical research study , you will be provided
with the established standard treatment for PAH available at your clinic / hospital . There may also
be other clinical research studies that you can choose to participate in. You can discuss these
alternatives with your doctor and decide if you want to participate in this study.
 
PARTICIPATION / VOLUNTARY WITHDRAWAL FROM THE STUDY
 
Your participation in this study is completely voluntary. You can refuse to participate or withdraw
from the study at any time without penalty or loss of benefits to which you are entitled. Your
decision will also not affect your treatment or your relationship with the people treating you
at the clinic / hospital . Your participation may also be stopped without your consent if your doctor
considers it to be in your best interest. The sponsor can also stop this study at any time.
 
CONFIDENTIALITY OF RECORDS
 
The confidentiality of your records will be maintained to the extent possible. Monitors and
other members of the study staff representing the Sponsor , the Ethics Committee / Institutional
Review Board, and regulatory authorities, such as the General Directorate of Medicines, Supplies
and Drugs (DIGEMID) and the National Institute of Health (INS ) of Peru will have direct access to
their original medical records to the extent permitted by applicable laws and regulations, to verify
both the clinical trial procedures and the data they contain .
 
By signing this informed consent form you or your legal representative give your authorization
for such access.
 
Your permission to use and disclose your health information will not expire. You may revoke your
authorization at any time by sending a written notice to the study doctor. If you withdraw your
permission, you will not be able to continue in this study. When you withdraw your permission, no
new medical information that could identify you will be generated after that date.  Information that
has already been collected can still be used and released to others , unless you request in writing
that all previously retained data be destroyed to prevent future analysis, in accordance with national
regulations , and as long as such destruction does not is detrimental to the integrity of the
study . You have the right to inspect and copy your health information. However, if you decide to
participate in this study and sign this informed consent, you will not be able to see or copy your
information until after the study is completed.
 
Your doctor will inform you of the results of the study after the investigation is completed.
 
In the same way, at the end of this study worldwide , the results of the study will be available
in the various regulatory bodies nationals, including the INS in the case of Peru , qu and will
have information available in Spanish on this website , http : //www.ins.gob.pe . Also, you can ask
the researcher about the results of the study. You will not be identified in any of these
publications or reports.
 
The information obtained from this study, including the results of all tests that were performed , be
placed on file systems both computerized and manual, although these are not what they
identified by name. These records can be used for product registration purposes and will
therefore be available to health authorities around the world , and can be sent abroad , for example
to Europe or the USA to be processed either by company personnel or by third
parties . These records will only be kept for as long as is necessary and during that time will
remain confidential and, to the extent permitted by applicable laws and regulations, will not be
made available to the public. If the test results are published , your identity will be kept
confidential. Any identifying information ( name, address, etc. ) will be removed from all
records before being released to the sponsor . You will not be identified personally in any
presentation or report trat and of research.
 
Your blood samples will be analyzed in the central laboratories, the information provided to the
laboratories will not identify you by name.
 
If you give permission to release your identifiable health information to a person or business other
than those covered by federal regulations, the information may not be protected by federal
privacy regulations . As a consequence, there is a risk that your information will be disclosed to
third parties without your authorization.
 
 
COSTS AND COMPENSATION
 
You will not receive any payment for your participation in the study . The medication
study , visits , and all tests laboratory related to the study are provided free of charge .
 
If your participation in the study will cause some costs , such as transportation, communication or
food s that have to take the medical center, they will be covered by the sponsor and will be
reimbursed by the investigator of the study . The amount to be refunded not
exceed the S / . 100 new soles per visit.
 
WHO IS FUNDING THIS STUDY?
 
A company called , Actelion Pharmaceuticals Ltd . , The sponsor of the study, is paying for this
study and pay to the doctor / institution of the study to carry it out.
 
COMPENSATION / TREATMENT FOR INJURIES RELATED TO RESEARCH
 
Your health is our main concern. In the unlikely event that you are injured as a result of your
participation in this study, your doctor will provide you
with usual or usual medical care or hospitalization . In case of an injury as a direct result of the
treatment or procedure s of the study and provided study medication is administered according to
the protocol , you will be covered by insurance sponsor . This insurance will cover all medical
expenses that the study participant requires for their care, apart from those that their usual insurance
covers, including hospitalization. These medical expenses will be covered according to
the Sponsor's insurance policy in Peru (Rímac Seguros) . This policy will be valid until the end of
the study. No other compensation is offered.
 
As established by Peruvian law, you, your family, and your dependent family members will receive
compensation in the event of disability or death that results directly from the procedures related to
the study.
 
NEW FINDINGS
 
The study doctor or study staff will inform you of any new information about the study
drug that becomes available that may affect your decision to continue in this study. You may be
asked to sign a new ( revised) informed consent to document that you have been informed of this
new information .
 
HOW TO GET ADDITIONAL INFORMATION
 
We encourage you to ask questions at any time during the study . If you experience a side effect or
if you have any questions about the study , please contact the study physician (see contact details on
page 1) :
 
If you have any questions about your rights as a study subject , or in the event of a study-
related injury , you can contact:
 
_________________________________ at ___________________________________
[ The representative of the IRB / EC , according to CFR 21 part 56] :
 
If you consider that your rights are violated or you have any complaint, you
can contact the National Institute of Health ( General Office for Research
and Technology Transfer , OGITT ), regulator of clinical trials , through the following telephone
number 748- 1111 extension 21 91 or by writing or to the following
email : consultaensayos@ins.gob.pe or by means of a formal document presented to the institution
or go personally to the OGITT at the following address : Cápac Yupanqui 1400, Jesús María ,
Lima 11.
 

INFORMED CONSENT
GRIPHON: Prostacyclin (P G I  ) R eceptor agonist I n P ulmonary arterial H ypertensi ON ( pros
2 

tacyclin receptor agonist [PGI2] in pulmonary arterial hypertension)

Long-term, single-arm, open- label study to evaluate the safety and tolerability

of selexipag (ACT-293987) in patients with pulmonary arterial hypertension.
 

I confirm that the clinical study has been explained to me in the following
language: __________________ (to be completed by the subject or their legal representative only),
that I can fully understand this language and that I was therefore able to make an informed decision.
I have read and understand the purpose of the study, as well as the possible benefits and risks of
participating in the study. I have had the opportunity to ask questions , and my questions have been
answered . I hereby give my informed consent to be a participant in this study. I understand
the possible adverse reactions that may be induced by the selexipag study drug . I received a copy
of the Prospectus for the S ubject . I realize that I will receive a copy of this C onsentimiento I I
nformado duly signed .
I understand that signing this consent form authorize access to my medical records
to the monitor and s and auditore s representing the P atrocinador , and possibly members of
the Ethics Committee / Review Board Institutional or authorities regulatory , for the verification of
the clinical procedures of the study and / or data . I agree that my primary care physician is
informed about my participation in the study .
Also I am aware that the information obtained in this study , including the results of all
tests on m i person, be consignad to in file systems both computerized and manual, but
not me identify by name. These records can be used for product registration purposes and
therefore can be made available to health authorities around the world , and can be sent abroad for
processing by any company personnel or third parties .
I understand that I am free to withdraw from the study :
 anytime
 without having to give a reason for my withdrawal
 without affecting my future medical care
 
Patient: _______________________ ________________ ___________
_______                                                       
                                          Name Signature Date Time                                                                                                      
                               
 
 
I, the undersigned, have fully explained the relevant details of this study to the above-
mentioned patient , or to the person authorized to give consent for the subject .
 
Researcher or delegate: _______________________ __________________ _____________
_____             
                                          Name               Signature Date  
Time                                                                                                                           
 
 
Reminder:   A  signed copy of this consent form will be given  to  the patient
Informed Consent / Information for the subject GRIPHON OL_Versió n 10 2017 _Perú _Version
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