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16.statistics 16.1 description of statistical

If continuous variables are transformable to normal, they will be power-transformed and independent, two sample t-tests will be used for analysis of continuous variables. If data are not transformable to normal, non-parametric t-test equivalents (e.g. Wilcoxon signed rank and rank sum test, Mann-Whitney test and analysis of covariance (ANCOVA)) will be used. Chi-squared (or Fisher Exact) analyses will be used to compare categorical variables. Two-sided p values <0.05 will denote significance, with adjustment for multiplicity using Holm procedure. If required, missing data will be addressed using multiple imputation using chained equations as previously described (Ledwidge et al. JAMA. 2013;310(1):66-74) and results will be presented (primary and secondary end points) as pooled results from the multiple imputed data sets using a last-observation carried-forward analysis.  
Demographics and clinical characteristics will be summarized with descriptive statistics (counts and percentages for categorical variables, or mean value ± the standard deviation for normally distributed continuous variables, or medians and interquartile ranges for non-normally distributed continuous variables).Repeated marker changes from baseline to 18 months will be analysed using ANOVA with repeated measures models. Primary and secondary outcome measures will be performed both with and without adjustment for the effects of age, sex, diabetes, hypertension, obesity, and vascular disease. Further models will include adjustment for baseline measures of the outcome of interest (e.g. LAVI, BNP). Categorical endpoints will be analyzed using generalized linear modeling with a binomial outcome distribution for prevalence and a Poisson outcome distribution for incidence rate (adjusted for patient-years). The multivariable models will include both prespecified covariates (age, sex, diabetes, hypertension, obesity, and vascular disease) and those variables with univariate P values ≤ 0.25. The likelihood ratio test and the Nagelkerke R Square will be used to identify independent variables with low explanatory power and to assess the fit of each specification of the multiple regression models.
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16.2 determination of sample size

Based on the endpoint of change in LAVI over 18 months, the PARABLE trial aims to recruit 250 subjects (125 per arm). The current STOP-HF database includes 1499 subjects with cardiovascular risk factors. An additional cohort of just under 1000 subjects has been recruited from the STOP-HF outreach service and is available for screening and recruitment into the study. The STOP-HF Investigators are also working with other clinical trial units and can incorporate additional centres if required to achieve timely recruitment. Sample size estimates were calculated from the current STOP-HF subject database
(n=1499). A subsample of subjects with BNP > 50 pg/mL, LAVI > 28 mL/m2, with normal EF (≥ 50%) and in normal sinus rhythm was drawn. This resulted in a population of 163 (11%) of the total with a population BNP of 125 pg/mL and a baseline mean LAVI of 36.2 mL/m2 (standard deviation of 6.9 mL/m2) determined by Doppler 10.0 Effective date: 18.2.2021 Page 63 of 86  
  
Echocardiography. This LAVI is reassuringly similar to the baseline level observed by Solomon et al. (Lancet 2012; 380: 1387–95) in the PARAMOUNT study, which observed a 36-week drop in LAVI of 2.6 mL/m2, and assuming the control group-shows no decrease in LAVI (as in Solomon et al. 2012 paper), the expected effect size in a similar study is 2.6/6.5 = 0.38. Setting alpha = 5% (two-tailed), beta = 20% and using an independent t-test to assess the change in LAVI over follow-up, the required number of subjects to detect this effect is 222 (111 per study arm), or 248 after accounting for a 10% dropout rate. In a review of the expected effect size, once blinded echocardiography was available for 125 patients at the 9-month time point, it was noted that the actual standard deviation of baseline to 9-month change scores was 4.7. This means an expected effect size of at least (2.0/5.0) = 0.40. An effect size of 0.4 would require 96 patients in each group, suggesting that the study is adequately powered on LAVI assessed by echocardiography. In addition, the study has at least 80% power with a two-tailed alpha = 5% to detect a 6 g/m2 difference in LVMI change by CMRi, a 2.5 mL/m2 in LAVI change by CMRi, a 2-unit difference in E/e' or e' using Tissue Doppler measurements.
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17.direct access to source data/documents

Direct access will be granted to authorised representatives from the Sponsor, host institution and the regulatory authorities to permit trial-related monitoring, audits and inspections.
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18.data handling and record keeping

Source documents for this study will include hospital records, procedure reports and data collection forms (e.g. questionnaires). These documents will be used to enter data on the CRFs.  
A paper CRF will be used for this study. All data entered on CRFs must be entered legibly. If an error is made, the error will be crossed through with a single line in such a way that the original entry can still be read. The correct entry will then be clearly inserted and the alterations will be initialled and dated by the Investigator. Data reported on the CRF that are derived from source documents must be consistent with the source documents or the discrepancies must be explained. In some instances it is acceptable to file a copy of the source document (e.g. blood report, ABPM readout) in the study file and to cross-reference to the source document in the CRF.  
The monitor must make certain that all data are completed on the CRF. After comparing the data to the source documents, the monitor will request correction/clarification from the Investigator. After the last visit of the subject, the Investigator must attest the authenticity of the data collected in the CRF by signing the appropriate section of the CRF.  
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All documents will be stored safely in a confidential manner. On all study-specific documents, other than informed consent, the subject will be referred to by the subject study number/code.
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18.2 data reporting

Subjects will be identified by a study specific subject number in the database. The name and any other identifying detail will not be included in any study data electronic file.
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19.retention of essential documents

Essential documents will be retained until at least 15 years after the publication of the clinical study report. These documents will be retained for a longer period however, if required by the applicable regulatory requirements or by agreement with the Sponsor. The Investigator should retain the trial-related essential documents as required by the applicable regulatory requirements and until the Sponsor informs the Investigator these documents are no longer necessary.
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20.quality control and quality assurance

The study will be conducted in accordance with the current approved protocol, ICH good clinical practice (GCP), relevant regulations and applicable SOPs.
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20.1 before the study

The Investigator will allow the monitor to visit the site and facilities where the study will take place in order to ensure compliance with the protocol requirements. Training sessions will be organised for the Investigators/study team on the study protocol.
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20.2 during the study

For all participants who give informed consent, regardless of whether or not they receive any study drug, the Investigator designee will record participant identification data in the "Participant Identification List" (full name, initials, date of birth, participant identification code) or other similar list. The participant identification list will allow for the definite identification of any research participant that takes part in the study. A statement acknowledging the participation of a research participant in this clinical study will be also documented in the participant's medical file/notes. To protect the research participant's identity a unique identification code (randomisation number/study ID) will be assigned by WebEz to each study participant and used in lieu of the participant's name when AEs and/or other study-related data are reported. This coded form of identification, instead of the participant's name, will appear on all documents/databases and will be cross-referenced by the participant's 10.0  
  
date of birth. Documents not for submission to Sponsor, such as the confidential participant identification list and the signed Informed Consent Forms, will be kept in strict confidence on site and will not be removed from site.  
Personal information will be treated as confidential but may need to be reviewed by authorised representatives of the Sponsor - such as monitors and auditor/inspector from the ECs and the regulatory authorities. The participant's consent to direct access to his/her original medical records for data verification purposes will be obtained, via the informed consent process prior to that participant's participation in the study. The Investigator will permit the Sponsor, authorised agents of the Sponsor (such as monitors, auditors, etc.), the Contract Research Organization, and regulatory agency employees to enter and inspect any site where the drug or records pertaining to the drug are held, and to inspect and copy all records relating to an investigation, including research participant records. The Investigator will make available all CRFs for review by the Sponsor, study monitor, and the regulatory agencies as necessary. To ensure the accuracy of data submitted, it is mandatory that representatives of the Sponsor and of the regulatory agencies have access to source documents (i.e. participant medical records or notes, charts, laboratory reports, etc.). Participant confidentiality will be protected at all times. The Investigator will allow the monitor to:  
- inspect the site, the facilities and the material used for the study
- meet all members of his/her team involved in the study
- consult all of the documents relevant to the study
- have access to the CRFs
- check that the CRFs have been filled out correctly
- directly access source documents for comparison of data therein with the data in the CRFs
- verify that the study is carried out in compliance with the protocol and local regulatory requirements
The study Investigators will adhere to hospital protocols pertaining to healthcare record use and storage. The Investigators and authorised designees will ensure that the confidentiality of the participants' data is preserved. On CRFs or any other documents submitted to the Sponsor's designee, the participant will be identified not by their names, but by their coded form of identification.
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21.audits and inspections

The trial may be subject to internal or external auditing or inspection procedure to ensure adherence to GCP. Access to all trial-related documents will be given at that time.  
A quality assurance audit may be conducted by the Sponsor or its agent at any time during, or shortly after, the study. The Investigator will permit an independent audit by an auditor mandated by Sponsor, after reasonable notice. The purpose of an audit is to confirm that the study is conducted as per protocol, GCP and applicable regulatory requirements, that the rights and well-being of the patients enrolled have been protected, and that the data relevant for the evaluation of the IMP have been captured, processed and reported in compliance with the planned arrangements. The Investigator will permit direct access to all study documents, drug accountability records, medical records and source data. Regulatory authorities may perform an inspection of the study up to several years after its completion. If an inspection is announced the Sponsor will be informed immediately.
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22.ethical considerations 22.1 ethical conduct

This study will be carried out in compliance with the Study Protocol and in accordance with the Sponsors SOPs. These are designed to ensure adherence to GCP guidelines, as described in:  
- International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonized Tripartite Guidelines for Good Clinical Practice 1996
- EU CT Directive 2001/20/EC
- GCP Commission Directive 2005/28/EC
- Declaration of Helsinki, concerning medical research in humans (1964)
including all amendments up to and including the 2013 revision
- National laws
The Investigator agrees, when signing the study protocol, to adhere to the instructions and procedures described in it and to the principles of GCP to which it conforms. The regulatory permission to perform the study will be obtained in accordance with applicable regulatory requirements. All ethical and regulatory approvals must be available before a patient is exposed to any study-related procedure, including screening tests to determine eligibility.  
  
The Sponsor will ensure that this study is conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki.
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22.3 good clinical practice

This study will be conducted in accordance with GCP, as defined by the ICH and in accordance with the ethical principles underlying EU Directive 2001/20/EC and 2005/28/EC.
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22.4 approvals

Before initiating this study, the protocol, SmPC, Investigators Brochure, Patient Information Leaflet and Informed Consent Form, and any other written information to be given to participants will be reviewed and approved by the competent authority and the EC. A signed and dated statement that all documents submitted for review have been approved by the EC will be given to the Sponsor or designee before the study can commence at a site. The membership and the constitution of the EC who approved the documents will be also supplied to the Sponsor or designee. The Sponsor/designee will submit and obtain approval from the above parties for substantial amendments to the original approved documents. Modifications of the signed protocol are only possible by approved protocol amendments and with the agreement of all responsible persons. The procedure for approval of a protocol amendment is identical to that for approval of the protocol. All substantial protocol amendment must be submitted to the Regulatory Authority and EC for approval. The changes in the protocol must not be instituted until the amendment and the revised informed consent (if appropriate) has been reviewed and received approval / favourable response from both the Regulatory Authority and EC. A protocol amendment intended to eliminate an apparent immediate hazard to participants may be implemented immediately providing that both the Regulatory Authority and EC are notified as soon as possible, and an approval is requested. Nonsubstantial protocol amendments may be implemented immediately.
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22.5 informed consent

The Investigator or his/her designee shall obtain written informed consent from each participant before his/her participation in the study and before any study related procedure is undertaken. Therefore, informed consent shall be obtained at Visit 1 before any study related procedure is performed. Prior to this, the Investigator or his/her delegate must inform each participant of the objectives, benefits, risks and requirements imposed by the study, as well as the nature of the study drugs. Informed consent must also be obtained for each patient to allow biobanking of blood samples. A separate signature page is included on the Participant Information and Consent  
 Form for this purpose. Only a qualified medical doctor may obtain informed consent. The participant will be provided with an information and consent form in clear, simple language. He/she must be allowed ample time to inquire about details of the study and to decide whether or not to participate in the study. The Investigator shall answer all questions the patient may have about the study. Two original information and consent forms must be completed, dated and signed personally by the participant and by the person responsible for collecting the informed consent. The participant will be given one signed original information and consent form, the second original will be kept by the Investigator. Any change to the information and consent form constitutes an amendment to this document and must be submitted for approval to the EC, and if applicable to the Regulatory Authorities. Such amendments may only be implemented after written approval of the EC has been obtained and compliance with the local regulatory requirements, with the exception of an amendment required to eliminate an immediate risk to the study participants. Each participant affected by the amendment or an independent witness must complete, date and sign two originals of the new version of the information and consent form together with the person who conducted the informed consent discussion. He/she will receive one signed original amendment to the information and consent form. The obtaining of informed consent and any pre-consent discussions should be documented in the patients' medical notes. The following should be recorded in the subject's medical file:  
- The date that the Informed Consent Form was given to the subject
- The date written informed consent was obtained
- The name of the person obtaining informed consent
- Any other relevant information regarding the consent process
For every patient recruited into the PARABLE clinical trial, a notification should be placed on the inside of the front cover of the patients' medical notes in order to identify the clinical trial. (The notification should record the study name, patients study ID, consent date, the 'end of patient participation date' which should be completed at visit 11, the name of the Principal Investigator and contact number of the research team).
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22.6 subject confidentiality

The trial staff will ensure that the participants' anonymity is maintained. The participants will be identified only by initials and a subject's identification number on the CRF and any database. All documents will be stored securely. The study will comply with the Data Protection Act.
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23.financing and insurance/indemnity

The Heartbeat Trust is the Sponsor and it will ensure that every Investigator is covered by a Clinical Trial Insurance, which shall remain in effect for the duration of the Agreement. All Investigators are qualified and practicing physicians and are thus insured by the clinical indemnity scheme.
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24.clinical study report and publication

The study report will be drafted by the Clinical Trials Manager of the HBT in compliance with the Sponsor's SOP. The Sponsor and the Chief Investigator must mutually agree on the final version. One copy of the final report must be dated and signed by the Chief Investigator and the Legal Representative of the Sponsor.
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24.2 publication policy

The results of this study will be published in a high-quality clinical journal. The results of this study may provide the impetus for further research into the management of asymptomatic patients with risk factors for heart failure with LCZ696. The responsibility for publication of the data obtained from this study lies with the Investigator. Neither the Sponsor, nor any of the study funders, will have any involvement in data collection, data review, data analysis or preparation of the publication manuscript or in the decision to submit for publication. Submission of any publication manuscript may take place only with the permission of Prof. Kenneth McDonald, Consultant Cardiologist, and Dr Mark Ledwidge, Director of Research, St. Vincent's University Hospital, Dublin 4.
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25.study planning and schedule

The project milestones are as follows:
1. Clinical trial application to the HPRA 2. St Vincent's University Hospital Ethics application 3. Selection of suitable subjects from the STOP-HF data base and STOP-HF
Service in St Michael's Hospital 4. Informed consent from subjects 5. Recruitment of patients and inclusion in the study 6. Final evaluation 7. Data analyses 8. Manuscript preparation 9. Publication and presentation of results
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25.1 timelines and study duration

Start date: FPFV: 16 December 2015 End date:
- 18-month treatment period: LPFV: December 2018. FPLV: Oct 2017 and LPLV: December 2020
- 9- month follow-up (regression) substudy: FPFV: July 2019; LPLV: May 2021 Study Report date: CSR to be made available within 12 months after study completion.
26.appendices
25.1 timelines and study duration

Appendix 1. **Montreal Cognitive Assessment (MoCA)**
Montreal Cognitive Assessment Basic_MoCA.pdf Appendix 2. Standardised Mini-Mental State Examination SMMSE)
Standardised MMSE.pdf 10.0 Effective date: 18.2.2021 Page 72 of 86
appendix 3. euroqol (eq-5d-5l) health
25.1 timelines and study duration

| Subject study ID:   | Subject initials:   |           |            |
|---------------------|---------------------|-----------|------------|
| Date of test:       | Visit number:       |           |            |
| ¨Baseline           |                     | ¨9 months | ¨18 months |  
Under each heading, please tick the ONE box that best describes your health TODAY.
appendix 3. euroqol (eq-5d-5l) health
mobility

I have no problems in walking about q I have slight problems in walking about q I have moderate problems in walking about q I have severe problems in walking about q I am unable to walk about q
appendix 3. euroqol (eq-5d-5l) health
self-care

I have no problems washing or dressing myself q I have slight problems washing or dressing myself q I have moderate problems washing or dressing myself q I have severe problems washing or dressing myself q I am unable to wash or dress myself q USUAL ACTIVITIES *(e.g. work, study, housework, family or leisure activities)*
I have no problems doing my usual activities q I have slight problems doing my usual activities q I have moderate problems doing my usual activities q I have severe problems doing my usual activities q I am unable to do my usual activities q
appendix 3. euroqol (eq-5d-5l) health
pain / discomfort

I have no pain or discomfort q I have slight pain or discomfort q I have moderate pain or discomfort q I have severe pain or discomfort q 10.0 Effective date: 18.2.2021 Page 73 of 86  
  
The best health  
 you can imagine 100 I have extreme pain or discomfort q
appendix 3. euroqol (eq-5d-5l) health
anxiety / depression

I am not anxious or depressed q I am slightly anxious or depressed q I am moderately anxious or depressed q I am severely anxious or depressed q I am extremely anxious or depressed q 65 85 95 70 90
- We would like to know how good or bad your health is TODAY. - This scale is numbered from 0 to 100.  
- 100 means the best health you can imagine.  
0 means the worst health you can imagine.  
- Mark an X on the scale to indicate how your health is TODAY.  
- Now, please write the number you marked on the scale in the box below.  
  
  
10 The worst health you can imagine 0  
  
20 30 40 50 60 80 5  
  
15 25 35 45 55 75
appendix 3. euroqol (eq-5d-5l) health
appendix 4. montreal cognitive assessment

The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation.  
Time to administer the MoCA is approximately 10 minutes. The total possible score is 30 points; a score of 26 or above is considered normal.
appendix 3. euroqol (eq-5d-5l) health
1. alternating trail making

Administration: The examiner instructs the subject: "Please draw a line, going from a number to a letter in ascending order. Begin here [point to (1)] and draw a line from 1 then to A then to 2 and so on. End here [point to (E)]."
Scoring: Allocate one point if the subject successfully draws the following pattern: 1 −A- 2- B- 3- C4- D- 5- E, without drawing any lines that cross. Any error that is not immediately self-corrected earns a score of 0.
appendix 3. euroqol (eq-5d-5l) health
2. visuoconstructional skills (cylinder)

Administration: The examiner gives the following instructions, pointing to the cylinder: *"Copy this* drawing as accurately as you can, in the space below". Scoring: One point is allocated for a correctly executed drawing.  
- Drawing must be three-dimensional
- All lines/ovals are drawn
- No line is added
- The horizontal lines are relatively parallel. - The objects at the end must be ovals rather than circles.  
- The horizontal lines must touch the top/bottom of the ovals.
A point is not assigned if any of the above-criteria are not met.
appendix 3. euroqol (eq-5d-5l) health
3. visuoconstructional skills (clock)

Administration: Indicate the right third of the space and give the following instructions: *"Draw a* clock. Put in all the numbers and set the time to ten past nine".  
Scoring: One point is allocated for each of the following three criteria:  
- Contour (1 pt.): the clock face must be a circle with only minor distortion acceptable (e.g., slight imperfection on closing the circle);
- Numbers (1 pt.): all clock numbers must be present with no additional numbers; numbers must be in the correct order and placed in the approximate quadrants on the clock face; Roman numerals are acceptable; numbers can be placed outside the circle contour;
- Hands (1 pt.): there must be two hands jointly indicating the correct time; the hour hand must be clearly shorter than the minute hand; hands must be centred within the clock face with their junction close to the clock centre.
A point is not assigned for a given element if any of the above-criteria are not met.  
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appendix 3. euroqol (eq-5d-5l) health
4. naming

Administration: Beginning on the left, point to each figure and say: *"Tell me the name of this animal"*.  
Scoring: One point each is given for the following responses: (1) donkey (or mule); (2) pig (or hog); (3) kangaroo.
appendix 3. euroqol (eq-5d-5l) health
5. memory

Administration: The examiner reads a list of 5 words at a rate of one per second, giving the following instructions: *"This is a memory test. I am going to read a list of words that you will have to remember* now and later on. Listen carefully. When I am through, tell me as many words as you can remember.  
It doesn't matter in what order you say them."
Mark a check in the allocated space for each word the subject produces on this first trial. When the subject indicates that (s)he has finished (has recalled all words), or can recall no more words, read the list a second time with the following instructions: *"I am going to read the same list for a second* time. Try to remember and tell me as many *words as you can, including words you said the first time."* Put a check in the allocated space for each word the subject recalls after the second trial. At the end of the second trial, inform the subject that (s)he will be asked to recall these words again by saying,
"I will ask you to recall those words again at the end of the test."
Scoring: No points are given for Trials One and Two. Scoring is based on the delayed recall trial.
appendix 3. euroqol (eq-5d-5l) health
6. attention

Forward Digit Span: Administration: Give the following instruction: *"I am going to say some numbers* and when I am through, repeat them to me exactly as I said them". Read the five number sequence at a rate of one digit per second.  
Backward Digit Span: Administration: Give the following instruction: "Now I am going to say some more numbers, but when I am through you must repeat them to me in the backwards order." Read the three number sequence at a rate of one digit per second.  
Scoring: Allocate one point for each sequence correctly repeated, (N.B.: the correct response for the backwards trial is 4-7-1).
appendix 3. euroqol (eq-5d-5l) health
7. vigilance

Administration: The examiner reads the list of letters at a rate of one per second, after giving the following instruction: "I am going to read a sequence of letters. Every time I say the letter A, tap your hand once. If I say a different letter, do not tap *your hand".*
Scoring: Give one point if there is zero to one errors (an error is a tap on a wrong letter or a failure to tap on letter A).
appendix 3. euroqol (eq-5d-5l) health
8. serial 7s

Administration: The examiner gives the following instruction: "Now, I will ask you to count by subtracting 7 from 80, and then, keep subtracting 7 from your answer until I tell you to stop." Give this instruction twice if necessary.  
  
Scoring: This item is scored out of 3 points. Give no (0) points for no correct subtractions, 1 point for one correction subtraction, 2 points for two-to-three correct subtractions, and 3 points if the participant successfully makes four or five correct subtractions. Count each correct subtraction of 7 beginning at 80. Each subtraction is evaluated independently; that is, if the participant responds with an incorrect number but continues to correctly subtract 7 from it, give a point for each correct subtraction. For example, a participant may respond "72 - 65 - 58 - 51 - 44" where the "72" is incorrect, but all subsequent numbers are subtracted correctly.  
This is one error and the item would be given a score of 3.
appendix 3. euroqol (eq-5d-5l) health
9. sentence repetition

Administration: The examiner gives the following instructions: "I am going to read you a sentence. Repeat it after me, exactly as I say it [pause]: She heard his lawyer was the one to sue after the accident."
Following the response, say: *"Now I am going to read you another sentence. Repeat it after me, exactly* as I say it [pause]: *The little girls who were given too much candy got stomach aches."*
Scoring: Allocate 1 point for each sentence correctly repeated. Repetition must be exact. Be alert for errors that are omissions (e.g., omitting "too much") and substitutions/additions (e.g., " . . . his lawyer sued after . . ."; "the girls"), altering plurals, etc.).
appendix 3. euroqol (eq-5d-5l) health
10. verbal fluency

Administration: The examiner gives the following instruction: "Tell me as many words as you can think of that begin with a certain letter of the alphabet that I will tell you in a moment. You can say any kind of word you want, except for proper nouns (like Peter or Paris), numbers, or words that begin with the same sound but have a different suffix, for example, love, lover, loving. I will tell you to stop after one minute. Are you ready? [Pause] Now, tell me as many words as *you can think of that begin* with the letter B. [time for 60 sec]. Stop." Scoring: Allocate one point if the subject generates 11 words or more in 60 sec. Record the subject's response in the bottom or side margins.
appendix 3. euroqol (eq-5d-5l) health
11. abstraction

Administration: The examiner asks the subject to explain what each pair of words has in common, starting with the example: *"Tell me how an orange and a banana are alike".* If the subject answers in a concrete manner, then say only one additional time: "Tell me another way in which those items are alike". If the subject does not give the appropriate response (fruit), say, "Yes, and they are also both fruit." Do not give any additional instructions or clarification. After the practice trial, say: *"Now,* tell me how an eye and an ear *are alike".* Following the response, administer the second trial, saying: "Now tell me how a trumpet *and a piano* are alike". Do not give any additional instructions or prompts.  
Scoring: Only the last two item pairs are scored. Give 1 point to each item pair correctly answered. The following responses are acceptable:  
- eye-ear = sensory organs, parts of the head, parts of the body; - trumpet-piano = musical instruments, you can play them.
The following responses are not acceptable: eye-ear = parts of the face.  
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appendix 3. euroqol (eq-5d-5l) health
12. delayed recall

Administration: The examiner gives the following instruction: "I read some words to you earlier, which I asked you to remember. Tell me as many of those words as you can remember." Make a check mark
( √ ) for each of the words correctly recalled spontaneously without any cues, in the allocated space.  
Scoring: Allocate 1 point for each word recalled freely without any cues.
appendix 3. euroqol (eq-5d-5l) health
13. orientation

Administration: The examiner gives the following instructions: *"Tell me the date today".* If the subject does not give a complete answer, then prompt accordingly by saying: "Tell me the [year, month, exact date, and day of the week]." Then say: "*Now, tell me the name of this place, and which city it* is in."
Scoring: Give one point for each item correctly answered. The subject must tell the exact date and the exact place (name of hospital, clinic, unit). No points are allocated if subject makes an error of one day for the day and date. TOTAL SCORE: Sum all sub-scores listed on the right-hand side. Add one point for an individual who has 12 years or fewer of formal education, for a possible maximum of 30 points. A final total score of 26 and above is considered normal.
appendix 5. adverse event handling.
13. orientation

Notification of an Adverse Event
(AE)  
  
Complete Serious
Adverse Event
(SAE) Report
(Signature of medical doctor Forward copy to
Sponsor within 24 Follow-up information
requested?
Complete new SE Report Form with new information only Forward copy to Sponsor within 24
HOURS
HBT-PTCL-01. Version 10.0 Effective date: 18.2.2021
appendix 6. adverse event handling.
appendix 7. clinically notable laboratory

Clinically notable laboratory abnormalities for selected tests based on a percent change from baseline:  
| Haematology  RBC count      | >50% increase   | >20% decrease   |
|-----------------------------|-----------------|-----------------|
| Haemoglobin                 | >50% increase   | >20% decrease   |
| Haematocrit                 | >50% increase   | >20% decrease   |
| WBC count                   | >50% increase   | >50% decrease   |
| Platelet count              | >75% increase   | >50% decrease   |
| Blood Chemistry  ALT (SGPT) | >150% increase  |                 |
| AST (SGOT)                  | >150% increase  |                 |
| BUN                         | >50% increase   |                 |
| Creatinine                  | >50% increase   |                 |
| Total bilirubin             | >100% increase  |                 |
| CPK                         | >300% increase  |                 |
| Alkaline phosphatase        | >100% increase  |                 |
| Sodium                      | >5% decrease    |                 |
| Potassium                   | >20% increase   | >20% decrease   |
| Chloride >10% increase,     | >10% decrease   |                 |
| Calcium >10% increase,      | >10% decrease   |                 |
| Uric acid >50% increase     |                 |                 |
appendix 6. adverse event handling.
appendix 8. treatment guidelines treatment

General principles: It is recommended that any subject with a serum K+ > 5.2 mEq/L
following randomization may require frequent checks of potassium concentration until it is clear that the potassium concentration is stable and not rising into the range of concern (> 5.5 and < 6.0 mEq/L) or potential danger (> 6.0 mEq/L).  
Investigators should not randomize a subject with a serum K+ > 5.2 mEq/L at Visit 1
(screening) and follow the other measures outlined below if K+ increases to values >
5.2 mEq/L after randomization.
appendix 6. adverse event handling.
corrective action recommended for management

- If necessary, confirm potassium concentration was obtained in a nonhaemolysed sampled. If it is confirmed that questionable results were obtained from haemolysed specimen, redraw blood sample for K+ measurement and caution should be taken to minimize the incidence of haemolysis by proper blood sample collection and handling
- Reinforce low potassium diet and restriction of food/drinks with high potassium content (e.g. orange juice, melon, bananas, low-salt substitutes, etc.)
- Review medical regimen (including dietary supplements and over-the-counter medications) for agents known to cause hyperkalaemia. Consider reduction in dose or discontinuation of these agents:
o Confirm that potassium-sparing diuretics and potassium supplements aren't being used o Salt substitutes o Non-steroidal anti-inflammatory drugs (NSAIDs)
o Cyclo-oxygenase-2 (COX-2) inhibitors o Trimethoprim and trimethoprim-containing combination products such as trimethoprim/sulfamethoxazole o Herbal Supplements: (for xample, Noni juice, alfalfa (Medicago sativa),
dandelion (Taraxacum officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily of the valley, Siberian ginseng, hawthorn berries)
appendix 6. adverse event handling.
k+ > 5.5 and <=

- If necessary, confirm potassium concentration was obtained in a nonhemolyzed sample
- Apply all measures outlined for K+ 5.2 and ≤ 5.5 mEq/L
- Repeat K+ measurement after 1-3 days - Discontinue the study drug if a repeated K+ > 5.5 mEq/L
appendix 6. adverse event handling.
k+ > 6.0 meq/l

- Immediately discontinue study drug
- Confirm potassium concentration in a non-haemolysed sample
- Urgently evaluate subject and treat hyperkalaemia as clinically indicated
- Apply all measures outlined for K+ > 5.2 and ≤ 6.0 mEq/L
appendix 6. adverse event handling.
guidelines for the management of

1. Treatment should not be initiated if systolic BP <100mmHg at screening or baseline. A lower starting dose (Level 1) should be considered for patients with systolic BP ≥100 to 110mmHg.  
2. Investigator should monitor blood pressure closely throughout the study 3. If systolic BP falls to ≤95mmHg (or symptomatic hypotension occurs at any BP):
- Correct any treatable cause, e.g. hypovolemia
- If symptomatic hypotension persists, consider down titrating or stopping other hypotensive medications, and/or study drug as appropriate.  
- If symptomatic hypotension persists during two consecutive office visits or as judged by the Investigator, discontinue the study drug.
appendix 6. adverse event handling.
guidelines for the management of

General principles: Some subjects may develop renal dysfunction after study drug administration. Two types of response to serum creatinine increase are described:
appendix 6. adverse event handling.
surveillance situation

If, at any moment after recruitment, serum creatinine increases by ≥50% from baseline (Visit 1), the Investigator will check for potentially reversible cases of renal dysfunction such as:
- NSAID intake, diuretics, antibiotics, or other treatments known to affect creatinine
- Volume decrease
- Urinary infection - Urinary tract obstruction - Study medication The Investigator should consider discontinuing any medication known to affect the renal function and should repeat the serum creatinine after 5-7 days.
appendix 6. adverse event handling.
action situation

If serum creatinine >3.0 mg/dL or increases by ≥100% from baseline (Visit 1), the Investigator will discontinue study drug and check for potentially reversible causes of renal dysfunction (see above). Thereafter, serum creatinine should be monitored until its resolution.  
10.0
appendix 6. adverse event handling.
appendix 9. parable. nine-month follow-up

The overall objective of the nine-month follow-up study is to evaluate if the treatment effects observed during the 18-month PARABLE study persist nine-months after study drug discontinuation (see Exploratory Objective No 4 in Section 10.1). Secondary and exploratory endpoints shall be evaluated in this sub-set of subjects (see Exploratory Endpoint No 10 Section 10.2).
appendix 6. adverse event handling.
2. eligibility criteria

All PARABLE participants that completed the 18-month follow-up period, and did not discontinue the study drug prematurely, will be eligible for inclusion in the follow-up study.
appendix 6. adverse event handling.
3. informed consent

The procedure for obtaining informed consent is outlined in Section 22.5 of the main PARABLE protocol. Informed consent shall be obtained from the participant prior to any study related assessment or procedure been conducted using the Participant Information Leaflet and Informed Consent Form for the follow-up study (HBT-GCPFM-39).
appendix 6. adverse event handling.
4. assessments and procedures

The following assessments and procedures will be carried out at the nine-month follow-up visit in the same manner they were conducted during the main PARABLE study (see section 12.4) of the study protocol).  
- Physical exam o Vital size (BP and pulse, height, weight and waist/hip circumference)
o Biochemistry
§ Urea & Electrolytes (U&E) including eGFR § Liver Function Tests (LFT) § Alkaline Phosphatase § Lipid profile § HbA1c § Iron studies o Haematology
§ Full blood count
- Urine for second messenger cGMP and ANP* - Blood for biomarkers*
- Serum BNP and NT-proBNP - Ambulatory blood pressure monitoring
- 12-lead ECG
- Echo-Doppler studies 10.0 Effective date: 18.2.2021 Page 84 of 86
- QOL questionnaire (EuroQol) and two cognitive function assessment tools  
  
*cryovials will be labelled with the following information:
- PAR-XXXX (where XXXX is the participants PARABLE study ID)
- The date the sample was taken - The type of sample (e.g. whole blood, lithium heparin, urine etc)
- Timepoint: 9M-FU
appendix 6. adverse event handling.
references

1. Ledwidge, M., et al., Natriuretic peptide–based screening and collaborative care for heart failure: The stop-hf randomized trial. JAMA, 2013. 310(1): p. 66-74.  
2. Huelsmann, M., et al., PONTIAC (NT-proBNP Selected PreventiOn of cardiac eveNts in a populaTion of dIabetic patients without A history of Cardiac disease): A Prospective Randomized Controlled Trial. Journal of the American College of Cardiology, 2013. 62(15): p. 1365-1372.  
3. Phelan D, et al., Modest Elevation in BNP in Asymptomatic Hypertensive Patients Reflects Sub-Clinical Cardiac Remodeling, Inflammation and Extracellular Matrix Changes. PLoS ONE, 2012. 7(11): p. e49259.  
4. Potter, L.R., S. Abbey-Hosch, and D.M. Dickey, *Natriuretic Peptides, Their* Receptors, and Cyclic Guanosine Monophosphate-Dependent Signaling Functions. Endocrine Reviews, 2006. 27(1): p. 47-72.  
5. Gardner, D.G., et al., Molecular Biology of the Natriuretic Peptide System:
Implications for Physiology and Hypertension. Hypertension, 2007. 49(3): p. 419426.  
6. Watson CW, Glezeva N, Horgan S, Gallagher J, Phelan D, McDonald K, Tolan M,
Baugh B, Collier P, Ledwidge M *Atrial tissue pro-fibrotic M2 macrophage marker* CD163+, gene expression of procollagen and B-Type Natriuretic peptide. J Am Heart Assoc. 2020;9:e013416.  
7. Hogg, K., K. Swedberg, and J. McMurray, *Heart failure with preserved left* ventricular systolic function: epidemiology, clinical characteristics, and prognosis. Journal of the American College of Cardiology, 2004. 43(3): p. 317-327..  
8. Querejeta, R., et al., *Increased Collagen Type I Synthesis in Patients With Heart* Failure of Hypertensive Origin: Relation to Myocardial Fibrosis. Circulation, 2004. 110(10): p. 1263-1268.  
9. Martos, R., et al., *Diastolic Heart Failure: Evidence of Increased Myocardial* Collagen Turnover Linked to Diastolic Dysfunction. Circulation, 2007. 115(7): p. 888-895.  
10. Ahmed, S.H., et al., *Matrix Metalloproteinases/Tissue Inhibitors of* Metalloproteinases: Relationship Between Changes in Proteolytic Determinants of Matrix Composition and Structural, Functional, and Clinical Manifestations of Hypertensive Heart Disease. Circulation, 2006. 113(17): p. 2089-2096.  
11. Nishikimi, T., N. Maeda, and H. Matsuoka, *The role of natriuretic peptides in* cardioprotection. Vol. 69. 2006. 318-328.  
12. Solomon, S.D., et al., The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. The Lancet. 380(9851): p. 1387-1395.