Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study)

Robert Shaddy; Charles Canter; Nancy Halnon; Lazaros Kochilas; Joseph Rossano; Damien Bonnet; Christopher Bush; Ziqiang Zhao; Paul Kantor; Michael Burch; Fabian Chen

Accepted Manuscript

Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (pANORAMA-HF study)

Robert Shaddy MD, Charles Canter MD, Nancy Halnon MD, Lazaros Kochilas MD, Joseph Rossano MD, Damien Bonnet MD, Christopher Bush PhD, Ziqiang Zhao PhD, Paul Kantor MD, Michael Burch MD, Fabian Chen MD PhD

PII: DOI:

Reference:

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Received date: Accepted date:

S0002-8703(17)30205-3 doi: 10.1016/j.ahj.2017.07.006 YMHJ 5481

American Heart Journal

8 June 2017 12 July 2017

Please cite this article as: Shaddy Robert, Canter Charles, Halnon Nancy, Kochilas Lazaros, Rossano Joseph, Bonnet Damien, Bush Christopher, Zhao Ziqiang, Kantor Paul, Burch Michael, Chen Fabian, Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study), American Heart Journal (2017), doi: 10.1016/j.ahj.2017.07.006

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Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study)

RCT# NCT02678312

Robert Shaddy, MD1, Charles Canter, MD2, Nancy Halnon, MD3, Lazaros Kochilas, MD4, Joseph Rossano, MD5, Damien Bonnet, MD6, Christopher Bush, PhD7, Ziqiang Zhao PhD7 , Paul Kantor, MD8, Michael Burch, MD9, Fabian Chen, MD PhD7

Children's Hospital Los Angeles, Los Angeles, CA, USA; 2Washington University, MO, USA; 3University of California Los Angeles, Los Angeles, CA, USA; 4Children's Health Care of Atlanta, Atlanta, GA, USA; 5The Children's Hospital of Philadelphia, Philadelphia, PA, USA; 6Necker Hospital University, Paris, France; 7Novartis Pharmaceuticals Corporation, Shanghai China (ZZ) and East Hanover, NJ, USA (FC), 8University of Alberta, Edmonton, Canada; 9Great Ormond Street Hospital for Children, London, UK,

Short title: Pediatric HF sacubitril/valsartan study design

Corresponding authors:

Robert Shaddy MD

Children's Hospital Los Angeles

4650 Sunset Blvd. MS#126, Los Angeles, CA 90027

Ph: 323.361.1571 | Fax: 323-361-3719

Email: rshaddy@chla.usc.edu

Fabian Chen MD PhD 1 Health Plaza

Novartis Pharmaceuticals Corporation

East Hanover, NJ 07936

Email: fabian.chen@novartis.com

Graphical abstract

Design of the two-stage, seamless, adaptive PANORAMA-HF study assessing the PK/PD, safety, and efficacy of sacubitril/valsartan versus enalapril in pediatric heart failure patients with systemic left ventricle and reduced left ventricular systolic function

sacubitrif/valsartan PKIPQ

0 4 mg/kg

6 to < 18 years

0 8 3.1

mg/kg mg/kg

0.8 3.1

mg/kg mg/kg

sacutaitrii/vaisartan bid N = 180

enaiaprii bid N = 180

Time (weeks)

.*! loa to 120"

199 20l|202'j 203 to 299 301 401 402 403 404" 405 406 407 411 412 413 414 415 418/499 220"

-3 0 2 4 6 8 12 16 32 36 40 44 48 52

—H-H—H-:-►

Epoch Screening

Period 1

Peri od 2

First PK dose Second PK dose Screening

PreRandomization

*Open label enalapril visits

**Optiona! visit

Doubie-bSitid epooh

bid, twice-weekly; m, month; mg, milligram; kg, kilogram; PD, pharmacodynamics; PK, pharmacokinetics

Study design of sacubitril/valsartan in Pediatric Heart Failure Abstract

Background: Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown.

Study Design: This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to < 18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to < 18 years; Group 2: 1 to < 6 years; Group 3: 1 month to < 1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy.

Conclusion: The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function.

Study design of sacubitril/valsartan in Pediatric Heart Failure Introduction

Pediatric HF is characterized by significant morbidity and mortality, frequent hospitalization, and poor quality of life. An estimated 12,000 to 35,000 children below age 19 are diagnosed with HF in the United States (US) each year.1' 2 Congenital malformations account for most of the HF burden in children, occurring in ~8 per 1,000 live births, of which, 1-2 per 1,000 develop HF. 3 Cardiomyopathy is the other main cause of pediatric HF in the presence of a structurally normal heart. Data from the US, Australia, United Kingdom, and Ireland suggest that the annual incidence of new-onset HF in children with cardiomyopathy is approximately 1 per 100,000. 4-6

Pediatric HF is a clinical and pathophysiologic syndrome that is caused by a structural and/or functional impairment of ventricular systole or diastole. Although the pathophysiology of pediatric HF is similar to adults, the underlying etiology is often different. There are differences in the clinical course and outcome of pediatric HF compared to adult HF patients, and these differences are not predicted by studies of adult HF patients. The etiology of pediatric HF plays a key role in the clinical course and outcome. The majority of pediatric HF is associated with the presence of a congenital heart disease despite the significant improvement offered by the current surgical interventions. 1 7' 8 Furthermore, nearly 40% of children in the US with HF due to cardiomyopathy undergo heart transplantation or die within 2 years of diagnosis.4

In contrast to HF in adults, there have been relatively few clinical trials performed in children with HF. As a result, the current treatment recommendations for children are mostly deduced from adult clinical data. The current clinical management of pediatric HF includes the use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), p-blockers, diuretics, aldosterone receptor antagonists, digoxin, and anticoagulants, all of which are based on adult HF clinical studies.9 None of these pharmacotherapies to date have demonstrated outcome benefits in children with HF in clinical trials.

The first, large randomized trial of pharmacotherapy in pediatric HF was published in 2007, in which carvedilol, a non-selective p-blocker and alpha-blocker, did not meet the primary endpoint of worsening HF and mortality in patients aged 8 months to 14 years despite the drug showing benefit in adult HF populations.10

Sacubitril/valsartan (also known by the Novartis designation LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor that has a novel mechanism of action providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the renin-angiotensin aldosterone (RAAS) system. After oral administration, sacubitril/valsartan is rapidly dissolved and yields sacubitril and valsartan. Valsartan is an angiotensin II type-1 receptor blocker that has previously been demonstrated to be beneficial for the treatment of adult HF.11 Sacubitril is a prodrug that is further hydrolyzed via esterases to sacubitrilat, a potent and selective NEP inhibitor. The level of circulating physiologically active natriuretic peptides increases due to NEP inhibition, resulting in enhancement of natriuretic, diuretic, and vasodilator actions. This simultaneous inhibition of both RAAS and NEP that corrects the imbalance of neurohumoral factors in HF is considered to be the mechanism by which sacubitril/valsartan benefits HF.

Sacubitril/valsartan is now approved in many countries for the treatment of adult patients with HF with reduced ejection fraction (HFrEF; New York Heart Association [NYHA] class II-IV). The landmark PARADIGM-HF trial in adult patients with HFrEF showed superior outcome benefits with sacubitril/valsartan over the comparable standard of care, the ACEI enalapril.12 In PARADIGM-HF, a 20% relative risk reduction for cardiovascular death and a 16% relative risk reduction for all-cause mortality was seen. Additionally, sacubitril/valsartan reduced both the risk of HF hospitalization and clinical progression versus enalapril. 12' 13

Safety analyses from the PARADIGM-HF trial demonstrated that sacubitril/valsartan was generally well tolerated compared with enalapril.12 Rates of study discontinuations for adverse events (AEs) were lower

for those patients randomized to sacubitril/valsartan compared with the enalapril group (10.7% versus 12.3%, p=0.03). Similarly, rates of renal impairment leading to study discontinuation, hyperkalemia, and cough were lower with sacubitril/valsartan than with enalapril. Although rates of symptomatic hypotension were higher with sacubitril/valsartan versus enalapril (14.0% versus 9.2%, p<0.001), the number of hypotension cases reported as serious adverse events was similar between groups (1.40% and 1.61% for sacubitril/valsartan and enalapril, respectively). Additionally, rates of confirmed angioedema, although numerically higher with sacubitril/valsartan than with enalapril (0.45% and 0.24%; p=0.13), remained low in both groups throughout the trial.12

Given the mortality and morbidity benefit of sacubitril/valsartan therapy over standard of HF treatment with enalapril demonstrated in adult HFrEF, the potential exists for similar superiority of sacubitril/valsartan for treatment of pediatric HF, especially for patients with similar pathophysiology to adult HFrEF. The pathophysiologic adaptation to decreased cardiac output for both adult and pediatric HF involves increased sympathetic tone and activation of the renin-angiotensin system.14 Similar to adult HF, pediatric HF results in increased activation of the natriuretic peptide system, and this pathophysiologic neurohumoral activation influences the progression of HF.15 Therefore, by modulating both RAAS and NEP in children with systolic HF, similar benefits are expected to those seen in adult HFrEF.

The purpose of the PANORAMA-HF study (Prospective trial to assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 versus ACEi for Medical treatment of Pediatric HF) is to determine if sacubitril/valsartan can offer a greater clinical treatment benefit compared to enalapril for pediatric HFrEF patients over 52 weeks treatment duration, as assessed using a global rank endpoint. This study will be conducted in two parts: Part 1, the dose determination study, will assess the pharmacokinetics (PK) and pharmacodynamics (PD) of sacubitril/valsartan following single ascending dose administration; and Part 2, the efficacy and safety study, will evaluate the superiority of sacubitril/valsartan over enalapril for the treatment of pediatric HF.

The innovative study design has been approved by the United States Food and Drug Administration (FDA) for the Proposed Pediatric Study Request (PPSR) and by the European Medicines Agency (EMA) for the Paediatric Investigation Plan (PIP). PANORAMA-HF began enrolling patients in November 2016 and is expected to complete in 2021. At the time of this manuscript submission (June 2017), Group 1 (6 to < 18 years, 8 patients) has completed the Part 1 PK/PD dose determination. This multinational study will encompass approximately 39 countries and 129 clinical sites that include North America, Europe, Asia, and Latin America.

Design of the study

This multicenter study will use an adaptive, seamless, two-part design (Figure 1), with Part 1 being a dose determination study and Part 2 being a clinical efficacy study (clinicaltrial.gov NCT02678312). The purpose of this seamless two-part design is to improve the efficiency of the study compared with a sequential approach involving two separate studies. This clinical study has been designed and shall be implemented, executed, and reported in accordance with the International Conference on Harmonization Harmonized Tripartite Guidelines for Good Clinical Practice and with the ethical principles laid down in the Declaration of Helsinki. 16

Study drug formulations

The sacubitril/valsartan medication will be available in three formulations: film-coated tablets, granules (mini tablets), or prepared liquid solution (made from granules or tablets). The film-coated tablets contain sacubitril/valsartan 50 mg, 100 mg or 200 mg (sacubitril/valsartan 24/26, 49/51, 97/103 mg respectively). The granules are film-coated, have a diameter of 2 mm, and contain sacubitril/valsartan 3.125 mg per granule.

The enalapril study medication will be available in two formulations: tablets or liquid formulation. The enalapril tablets contain enalapril 2.5 mg, 5 mg or 10 mg. The enalapril 1 mg/ml liquid formulation is made from the enalapril tablets.

The appropriate formulation will be used based on the patient's ability to take study medication (i.e. ability to swallow tablets) and based on the dose administered. Matching placebo will be used for both the sacubitril/valsartan and enalapril formulations.

Patients

The study will enroll at least 18 and up to 30 patients for Part 1, and at least 360 patients for Part 2. Male or female, inpatient or outpatient, pediatric HF patients (1 month to <18 years old) with systemic left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] < 40% or a fractional shortening < 20%) and receiving chronic HF therapy (if not newly diagnosed) are eligible for inclusion. The study will target enrollment of 25% ACEI/ARB-naive patients for Part 2 only. Major eligibility criteria include the following.

Inclusion criteria:

1. NYHA classification II-IV (older children: 6 to less than 18 years old) or Ross HF classification II-IV (younger children: less than 6 years old) at any time prior to screening

2. Biventricular physiology with a morphologic left ventricle supporting the systemic circulation

3. For Part 1 PK/PD, patients must be treated with an ACEI or ARB prior to screening. For Part 1 PK/PD, patients in age Group 1 and 2 must be treated with the dose equivalent of at least enalapril 0.2 mg/kg prior to the sacubitril/valsartan 3.1 mg/kg single dose assessment. Patients in age Group 3 must be treated with the dose equivalent of at least enalapril 0.1 mg/kg prior to the sacubitril/valsartan 1.6 mg/kg single dose assessment.

4. HF etiologies include: congenital cardiac malformation with systemic left ventricular systolic dysfunction, idiopathic cardiomyopathy, familial/inherited and/or genetic cardiomyopathy, history of myocarditis, neuromuscular disorder, inborn error of metabolism, mitochondrial disorder, acquired (chemotherapy, iatrogenic, infection, rheumatic, or nutritional), ischemic (e.g. Kawasaki disease and post-operative HF), and left ventricular non-compaction

5. Written informed consent by parent(s)/legal guardian(s) for pediatric patients must be obtained before any study-specific assessment is performed. A consent or assent may also be required for some patients depending upon their age and local requirement

Exclusion criteria:

1. Patients with single ventricle or systemic morphologic right ventricle.

2. Patients listed for heart transplantation as United Network for Organ Sharing (UNOS) status 1A (or equivalent status in non-UNOS countries) or hospitalized waiting for transplant while on inotropic agents or a ventricular assist device at the time of entry into the study.

3. Sustained or symptomatic dysrhythmias uncontrolled with drug or device therapy.

4. Patients that have had cardiovascular surgery or percutaneous intervention to palliate or correct congenital cardiovascular malformations within 3 months of the screening visit. Patients anticipated to undergo corrective heart surgery during the 12 months after entry into Part 2.

5. Patients with unoperated obstructive or severe regurgitant valvular (aortic, pulmonary, or tricuspid) disease, or with significant systemic ventricular outflow obstruction or aortic arch obstruction.

6. Patients with restrictive or hypertrophic cardiomyopathy.

7. Active myocarditis (diagnosed with presumed or acute myocarditis within 3 months of enrollment).

8. Symptomatic hypotension or systolic blood pressures (BP) below the calculated 5 th percentile systolic BP (SBP) for age at screening visit.

9. Renovascular hypertension (including renal artery stenosis).

10. Severe pulmonary hypertension (defined by pulmonary vascular resistance [PVR] index > 6 Wood units-m2) unresponsive to vasodilator agents (such as oxygen, nitroprusside, or nitric oxide). Note that measurement of PVR is not a requirement for study eligibility.

11. History or current clinical evidence of moderate-to-severe obstructive pulmonary disease or reactive airway diseases (e.g. asthma).

12. Serum potassium > 5.3 mmol/L at screening visits for Part 1 or Part 2.

13. Patients with significant renal dysfunction (estimated glomerular filtration rate calculated using the modified Schwartz formula < 30% for age and size), hepatic disorders (serum aspartate aminotransferase or alanine aminotransferase > 3 times the upper limit of normal), and gastrointestinal or biliary disorders (that could impair absorption, metabolism, or excretion of orally administered medications).

14. Concurrent terminal illness or other severe disease (e.g. acute lymphocytic leukemia) or other significant laboratory values that, in the opinion of the investigator, precludes study participation or survival.

15. Patients with a history of angioedema.

16. Patients with allergy or hypersensitivity to ACEIs/ARBs.

17. Women (females) of child-bearing potential who are pregnant, lactating, or sexually active and not taking adequate contraceptive precautions.

Study design of sacubitril/valsartan in Pediatric Heart Failure Study design

Part 1 dose determination

Part 1 is an open-label, single ascending dose study in pediatric patients (age 1 month to < 18 years) that will facilitate the prediction of multiple-dose PK exposure and determine the dose level to be used for Part 2 of the study. Part 1 will be conducted in selected countries and centers due to the limited number of patients required (total of at least 16 and up to 32 patients to complete 16 low dose and 16 high dose sacubitril/valsartan PK/PD assessments; note that a single patient can participate in the low and/or high dose sacubitril/valsartan PK/PD assessments). Eligible patients will be stratified into three age groups as follows: Group 1: 6 to < 18 years, Group 2: 1 to < 6 years, and Group 3: 1 month to < 1 year. Part 1 will be conducted in a sequential overlapping fashion and in a descending age group order such that subjects in the 6 to < 18 years age group will be dosed first. Depending on the PK, PD, and safety information from Group 1, the dose for Group 2 and subsequently for Group 3 will be adjusted. For Groups 1 and 2, there will be at least 6 PK/PD assessments each for the low and the high sacubitril/valsartan doses. For Group 3, there will be at least 4 PK/PD assessments each for the low and the high sacubitril/valsartan doses. The lower number of PK/PD assessments for the Group 3 (1 month to < 1 year) is due to the projected difficult enrollment of this age group.

Patients in Group 1 and 2 will receive a single dose of sacubitril/valsartan 0.8 mg/kg (low dose), and if well-tolerated, the patient can participate in the single dose sacubitril/valsartan 3.1 mg/kg (high dose) PK/PD assessment. Patients in Group 3 will receive a single dose of sacubitril/valsartan 0.4 mg/kg (low dose), and if well-tolerated, the patient can participate in the sacubitril/valsartan 1.6 mg/kg (high dose) PK/PD assessment. A patient may also participate directly in the higher dose sacubitril/valsartan PK/PD dose assessment. There is a minimum washout period of 5 days between the two dose assessments (to provide 5-10 half-lives to occur for the sacubitril/valsartan PK analytes to wash out between assessments). Patients receiving ACEIs should discontinue their ACEI at least 36 hours prior to

sacubitril/valsartan dosing to minimize the potential risk of angioedema due to overlapping ACEI and neprilysin inhibition. Similarly, patients should wait 36 hours after receiving sacubitril/valsartan prior to restarting ACEI to minimize potential risk of angioedema. Patients receiving ARBs should discontinue their ARB prior to the morning of the sacubitril/valsartan single dosing.

After completion of the PK/PD assessment visits, patients who agree to participate in Part 2 will be maintained on open-label enalapril or their standard of care HF medical regimen, which may include captopril, enalapril, or any other ACEI/ARB, until the initiation of Part 2.

Part 2 clinical efficacy

Part 2 is a 52-week, randomized, double blind, double-dummy, parallel group, active-controlled study to evaluate the efficacy, safety, and tolerability of sacubitril/valsartan compared with enalapril in pediatric patients with HF. A total of 360 eligible patients will be randomized to receive either sacubitril/valsartan or enalapril. Patients will be stratified by age group and NYHA/Ross functional classification and randomized using an interactive response technology system. Patients in Part 2 will include both patients who participated in Part 1 and new patients meeting the eligibility criteria. Patients receiving enalapril or other ACEIs are required to discontinue their medications at least 36 hours before receiving the blinded study drug at randomization.

The initial study drug dose started at randomization will be dose level 1 (for patients who are ACEI/ARB naive or on low-dose ACEI/ARB prior to randomization) or dose level 2 (for patients on higher doses of ACEI/ARB prior to randomization) (Table I). The target dose for sacubitril/valsartan is projected to be 3.1 mg/kg bid, and should not exceed 200 mg bid, irrespective of the body weight. The target dose for enalapril is 0.2 mg/kg bid (0.4 mg/kg total daily dose), with a maximum dose of 10 mg bid (20 mg total daily dose). The titration schema is shown in Table I, and progression to each next step will be based on overall safety and tolerability. In particular, patients will be titrated to the next dose level if there is no

symptomatic hypotension, hyperkalemia, or worsening renal function (Table II). Patients will continue to take any other background HF therapy, except for ACEIs and/or ARBs.

Table I Study drug dose levels for double-blind enalapril and sacubitril/valsartan in Part 2 efficacy study*

Dose levels for pediatric formulation Enalapril dose Sacubitril/valsartan dose*

Dose level 1 0.05 mg/kg bid 0.8 mg/kg bid

Dose level 2 0.1 mg/kg bid 1.6 mg/kg bid

Dose level 3 0.15 mg/kg bid 2.3 mg/kg bid

Dose level 4 0.2 mg/kg bid 3.1 mg/kg bid

Dose levels for adult formulation Enalapril dose Sacubitril/valsartan dose*

Dose level 1 2.5 mg bid 50 mg bid

Dose level 2 5 mg bid 100 mg bid

Dose level 3 7.5 mg bid 150 mg bid

Dose level 4 10 mg bid 200 mg bid

*Note: sacubitril/valsartan target dose (dose level 4) and other dose levels shown in the table are projected based on the target dose of sacubitril/valsartan 3.1 mg/kg bid. Sacubitril/valsartan target dose will be verified by Part 1 PK/PD and may be different for different age groups.

bid, twice daily; PD, pharmacodynamics; PK, pharmacokinetics

Table II Safety monitoring criteria for initiation/up-titration of study drug Parameter Description

Potassium level K+ < 5.4 mmol/L (mEq/L)

Kidney function eGFR (calculated using the modified Schwartz formula) > 30% for age eGFR reduction < 35% compared with randomization visit (Part 2)

BP SBP greater than the calculated 5th percentile SBP for age (1 month to

<1 year: 70 mm Hg; 1 year: 72 mm Hg; 2 years: 74 mm Hg; 3 years: 76 mm Hg; 4 years: 78 mm Hg; 5 years: 80 mm Hg; 6 years: 82 mm Hg; 7 years: 84 mm Hg; 8 years: 86 mm Hg; 9 years: 88 mm Hg; 1017 years: 90 mm Hg)

AEs or other No conditions that preclude study continuation according to the conditions investigator's judgment, including hypotension

AE, adverse event; BP, blood pressure; eGFR, estimated glomerular filtration rate; K+, potassium; SBP, systolic blood pressure

Study drug is titrated to dose level 4 as tolerated based on the safety monitoring criteria approximately every 2 weeks beginning at randomization (Visit 401; Figure 1) and continuing at Visits 402 and 403. Investigators have the option to schedule a patient for an additional visit (Visit 404; 6 weeks post-randomization) in order to complete the titration to the target dose (dose level 4). Unscheduled visits may be used to assess the patient and/or adjust study medication between scheduled visits as needed. After the 8 week post-randomization visit, there are scheduled monthly visits (Figure 1) that consist of a combination of telephone or office visits. However, patients must have an office visit and not a telephone visit at weeks 12, 24, 36, 48 and end of study.

Study design of sacubitril/valsartan in Pediatric Heart Failure Rationale for sacubitril/valsartan doses being tested in Part 1

Pediatric doses of renin angiotensin system blockers, which are used as standard of care in pediatric HF patients, are often calculated using body weight based on adult doses. The sacubitril/valsartan doses of 0.8 mg/kg (starting dose) and 3.1 mg/kg (projected target dose, to be confirmed by Part 1) are considered to correspond to the lowest dose (50 mg bid) and the maintenance dose (200 mg bid) for sacubitril/valsartan which have been approved for adult HF patients. The sacubitril/valsartan and 0.8 mg/kg and 3.1 mg/kg dose corresponds to the LCZ696 200 mg dose in adult subjects of 65 kg body weight.

The two single doses being examined for age Groups 1 and 2 are sacubitril/valsartan 0.8 mg/kg and 3.1 mg/kg, projected to be equivalent to adult sacubitril/valsartan 50 mg and 200 mg doses, respectively. Based on the decreased renal clearance of infants, there is a predicted increased exposure of sacubitril/valsartan in children under 1 year of age. Thus, the two single doses for age Group 3 planned are sacubitril/valsartan 0.4 mg/kg and 1.6 mg/kg. These doses are also projected to provide similar exposure in Group 3 to that seen with sacubitril/valsartan 50 mg and 200 mg in adult HF patients. As the three age groups will enroll sequentially, the dose for Group 3 may be adjusted depending on the safety, PK, and PD data available from age Groups 1 and 2. Given the difficult expected enrollment of Group 3 due to the increased vulnerability and significant blood volume restrictions for these infants, there will be four PK/PD assessments performed each for the lower and higher sacubitril/valsartan doses. Additional patients may be enrolled to obtain additional PK/PD observations as necessary after review of these data.

Rationale for enalapril comparator being tested in Part 2

Enalapril has been chosen as the comparator as it is a commonly used renin angiotensin system (RAS) blocker in children with HF. Additionally, enalapril is considered the standard of care in the treatment of chronic HF in most geographic areas.9' 17 Enalapril doses ranging from 0.1 to 0.5 mg/kg/day are used in the treatment of pediatric HF.

The dose of 0.4 mg/kg/day was the target dose in the 'Enalapril in infants with single ventricle' study,18 and is the target dose in the ongoing 'Labeling of enalapril from neonates up to adolescents', or LENA study.19 In addition, enalapril has a twice daily dosing regimen similar to sacubitril/valsartan. Two other commonly used ACEIs in pediatric HF are captopril and lisinopril. However, captopril is dosed three or four times daily and lisinopril is typically dosed once daily.

Dose Determination and Transition from Part 1 to Part 2

The decision on the dosing for each age group in Part 2 will be made by the independent Data Monitoring Committee (DMC) and Novartis after review of available data. The general criteria for assessing PK/PD and determining the dose are as follows.

• PK: The geometric mean of exposure of sacubitrilat (active metabolite of sacubitril) and valsartan will be compared with those in adult HF patients. The projected pediatric sacubitril/valsartan dose of 3.1 mg/kg bid is based on currently available adult pharmacokinetic data. The goal is to determine a pediatric dose that will provide similar exposures as in adult HF patients. The final sacubitril/valsartan target dose compared to the projected sacubitril/valsartan target dose may be adjusted and may be different between age cohorts depending on the Part 1 PK results.

PD: The exposure-response relationship of sacubitril/valsartan with PD markers (plasma cyclic guanosine monophosphate (cGMP), B-type natriuretic peptide (BNP), plasma N-terminal pro BNP (NTproBNP), and urine cGMP) in pediatric HF patients will be compared with that in adult HF patients to confirm the effect of NEP inhibition and RAAS inhibition of sacubitril/valsartan in pediatric HF patients. The PD markers chosen are downstream effectors of NEP inhibition. NEP degrades natriuretic peptides (NP) such as BNP and NTproBNP. NPs activate membrane-bound guanlyl cyclase-coupled receptors, resulting in increased cGMP. Therefore NEP inhibition with sacubitril/valsartan will result in increased NPs and its second messenger, cGMP.20

The exposure-response relationship will be evaluated by assessing PD at a low and high sacubitril/valsartan dose.

Safety and tolerability (AEs, laboratory findings, and vital signs) will also be considered to select the target dose.

Assessments

Pharmacokinetic (PK) and pharmacodynamics (PD) assessments

PK samples will be analyzed by WuXi AppTec (Shanghai, China). The following PK parameters will be determined using Phoenix version 6.2 or higher using non-compartmental methods for sacubitril/valsartan analytes (sacubitrilat and valsartan): maximum drug concentration (C^), time taken to reach the maximum concentration (T^), area under the curve from time zero to the last measurable concentration (AUQast), area under the curve from time zero to infinity (AUCmf), time required for drug concentration to decrease by half (T1/2), clearance (Cl/F), and other relevant parameters.

PD assessments will include plasma BNP, plasma NTproBNP and urine cGMP (analyzed by CRL Global Services, Lenexa, Kansas USA), and plasma cGMP (analyzed by SGS Cephac, Saint-Benoit Cedex, France).

Clinical efficacy measures

There is no agreed upon and validated clinical efficacy endpoint for pediatric HF. In addition, the low prevalence of chronic HF due to systemic left ventricle systolic dysfunction in pediatrics limits the ability to conduct large outcome trials using the conventional endpoints used in adult HF trials, such as death or worsening HF (e.g. HF hospitalization). The global rank endpoint used in this study was developed with

input and endorsement by pediatric HF experts, and builds on Packer's composite score with a methodology that further differentiates patients between treatment groups.21' 22 Packer's composite score has been widely used in adult cardiovascular clinical trials23' 24 in which the composite score classifies patients into three categories: worsened, unchanged, and improved. Thus, the global rank endpoint encompasses important clinical events grouped into broadly agreed upon categories of severity from mortality to disease progression (worsening HF) to measures of symptoms and physical functioning.

For the global rank endpoint used in this study, patients are classified into the 5 ordinal categories (Table III) and ranked from worst to best based on clinical events such as death, listing for urgent heart transplant, mechanical life support, worsening HF, measures of functional assessment in NYHA/Ross classification, and patient-reported outcomes. The patient-reported outcomes for the primary endpoint include the Patient Global Impression of Severity (PGIS) and the Pediatric Quality of Life Inventory (PedsQL; physical functioning sub-group of questions).

Patients with clinical event endpoints will be ranked within categories 1 and 2. An independent clinical events committee (CEC) will adjudicate clinical events for the primary endpoint (Supplementary appendix I). Category 1 includes death and other clinical endpoints such as ventricular assist device placement and UNOS status 1A (or equivalent) heart transplant listing that are scored equivalent to death. Patients who have a category 1 event will be further rank ordered based on the time to the first category 1 event. Patients who have a requirement for mechanical cardiopulmonary support at the end of the patient's one year study are also considered to have category 1 events.

Patients without a category 1 event will be considered category 2 if there is a worsening HF event (WHF). Patients with WHF will be subcategorized (worst to best subcategory) into patients with: (1) WHF with hospitalization with intensive care unit stay; (2) WHF with hospitalization without intensive care unit stay and (3) WHF without hospitalization (Table III). The patients will be further ranked based on time to first event and number of recurrent events.

Patients without a category 1 or 2 clinical event endpoint are ranked according to the change from baseline in clinician reported functional capacity (NYHA/Ross) and patient reported HF symptoms (PGIS), concordant with the hypothesis that sacubitril/valsartan will improve such inter-related parameters (Figure 2). The change from baseline for the NYHA/Ross and the PGIS are considered equal weight for rank ordering the patients within categories 3, 4, and 5. The patients will be ranked based on the sum of the degree of change for the NYHA/Ross and the PGIS. The PedsQL physical functioning domain will be used to further break ties between patient in age group 1 (6 to < 18 years old). The PedsQL physical functioning domain will be not be used for the global rank primary endpoint for patients less than 6 years old mainly given the preference for patient reported responses rather than parent/caregiver responses.

Secondary and explorative assessments comparing patient treatment with sacubitril/valsartan versus enalapril are listed in Table IV.

Table III Primary global rank endpoint

Category Sub- Description Ranking algorithm

category

4 F Unchanged NYHA/Ross and PGIS based Worst baseline combination of

on last available assessment compared to NYHA/Ross functional class and PGIS baseline without change is ranked worse than a

better baseline NYHA/Ross functional class and PGIS. Within a group of the same baseline NYHA/Ross and PGIS, further rank by PedsQL change from baseline

5 G Improved NYHA/Ross or PGIS improved Rank by combination of NYHA/Ross

(neither can be worse) based on last and PGIS degree of change. Within a

available assessment compared to baseline group of the same degree of NYHA/Ross

and PGIS change, further rank by PedsQL change from baseline

ECMO, extracorporeal membrane oxygenation; HF, heart failure; HFH, heart failure hospitalization; ICU, intensive care unit; NYHA, New York Heart Association; PedsQL, Pediatric Quality of Life Inventory; PGIS, Patient Global Impression of Severity; UNOS, United Network for Organ Sharing; VAD, ventricular assist device

Table IV Secondary and exploratory objectives and associated endpoints

Secondary assessments

To determine whether sacubitril/valsartan is superior to enalapril through 52 weeks double-blind treatment with regard to:

Delaying time to first occurrence of the composite of either Category 1 or 2 events Improving NYHA/Ross functional class Improving the PGIS score

To characterize the population PK of sacubitril/valsartan exposure in pediatric patients with HF during Part 2 efficacy (week 2, 12, 52) to estimate clearance and total exposure

To assess the safety and tolerability of sacubitril/valsartan compared to enalapril in pediatric patients with HF through 52 weeks of double-blind treatment

Secondary assessments

Exploratory assessments

To determine whether sacubitril/valsartan is superior to enalapril as assessed using the PedsQL through 52 weeks of double-blind treatment

To compare sacubitril/valsartan to enalapril on change in NTproBNP from baseline (randomization) to 12 weeks and from baseline to end of study (52 weeks)

To determine whether sacubitril/valsartan is superior to enalapril as assessed using the PGIC through 52 weeks of treatment

HF, heart failure; NYHA, New York Heart Association; NTproBNP, N-terminal pro B-type natriuretic peptide; PD, pharmacodynamics; PedsQL, Pediatric Quality of Life Inventory; PGIS, Patient Global Impression of Severity; PGIC, Patient Global Impression of Change; PK, pharmacokinetics

NYHA/Ross HFfunctional classification

The impact of study drug on the patient's physical functional status will be assessed using the NYHA classification I - IV (for older children: 6 to < 18 years old) or Ross HF classification I -IV (for younger children: l month to < 6 years old) (Supplementary appendix II). The NYHA and Ross functional class

17 23 25 28

assessments are reliable instruments for rating HF patients' functionality. ' ' -Patient global impression of severity (PGIS)

The PGIS was developed for this study to capture each patient's report of current HF symptoms over 7 days recall period (Supplementary appendix III). The patient PGIS report will be used for the global rank endpoint for patients that are > 5 years old.

Patient global impression of change (PGIC)

The PGIC was developed to capture each patient's current health status relative to their HF at the start of the study (Supplementary appendix III). At the baseline randomization Visit 401, the Investigator should call each patient's attention to how he/she feels about his/her HF condition at that time and explain that periodically throughout the study the patient will be asked to rate how he/she feels compared to at the randomization visit (Visit 401).

Pediatric quality of life inventory (PedsQL) 4.0 generic scales

The PedsQL is a patient-reported outcome instrument that evaluates health related quality of life in healthy children and adolescents and in pediatric patients with acute and chronic health conditions.29' 30 The PedsQL has published data in over 25,000 children and adolescents in multiple disease areas including pediatric cardiology.29' 31 The PedsQL has been validated in multiple pediatric disease populations and has demonstrated responsiveness to meaningful clinical change.31-33 The PedsQL is the most widely used pediatric patient reported outcome assessment, and it is currently being used in the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS) registry (INTERMACS protocol 2016)34' 35 and in an observational study of pediatric solid organ transplant recipients.36

This study will utilize the 23-item Generic Core Scales (which assesses physical, emotional, social, and school functioning). The physical functioning domain of questions that focuses on proximal effects of health-related quality of life related to HF will be used for the Global Rank primary endpoint. The responsiveness of the PedsQL physical functioning domain in pediatric patients with cardiovascular disease has been demonstrated in several studies. In a prospective study of 475 families including 347 children with cardiovascular disease, the PedsQL score for physical functioning by patient self-report was

significantly lower than the norms for healthy children.31 In this study, PedsQL physical functioning scores were also significantly lower for patients with more severe cardiovascular compared to milder cardiovascular disease. In a study of 126 families from Sweden with congenital heart disease, the PedsQL physical functioning scores were significantly lower for patients with more severe compared to mild/moderate congenital heart disease; and PedsQL physical functioning scores were also significantly lower comparing non-operated to operated congenital heart disease.37 PedsQL physical functioning scores were significantly lower for children who received a heart transplant compared to healthy peers and children who received curative heart surgery.38 Another study demonstrated that children with the more severe condition of hypoplastic left heart syndrome had significantly lower PedsQL physical functioning scores compared to the less clinically severe tetralogy of Fallot pediatric patients.39

Safety analyses

Safety assessments will include regular safety laboratory evaluations and assessment of body weight, vital signs SBP, diastolic blood pressure (DBP), pulse rate (PR), electrocardiogram (ECG) monitoring, adverse events (AEs), and serious adverse events (SAEs).

Identified risks with sacubitril/valsartan and enalapril, such as hypotension, hyperkalemia, worsening renal function, and angioedema, will be closely monitored. Dose-level adjustments of concomitant or study medications or interruption of study medications will be made in patients who are unable to tolerate the protocol-specified dosing scheme.

Data analysis and statistical considerations Part 1: Dose determination

For each age group and each analyte, the geometric mean clearance and 95% CI will be determined. A total of 12 observations for an age group is expected to have an 80% probability that the 95% CI of the point estimate for the geometric mean estimates of clearance and volume of distribution will be between

60% and 140% range (95% CI: 71%-141%). The sample size has been estimated assuming a 49.6% coefficient of variation (CV) based on a prior observed CV% for body weight-normalized clearance (39.4%) and volume of distribution (49.6%) of valsartan in adult HF patients.

Part 2: Clinical efficacy

Patients will be randomized within each stratum, where the stratum will be constructed based on age group and NYHA/ROSS class group [Class I/II, Class ID/TV].

The primary endpoint is the global rank endpoint, which first ranks patients in each stratum according to the 5 disease-severity-based categories (Table III). The entire patient population is then ranked from worst to best patient based on the 5 categories and then further rank ordered within each of the 5 categories.

The primary analysis will be the stratified Mann-Whitney analysis,40 based on the weighted sum of the within-stratum global rank-sum statistics.

The secondary endpoints include the time to first adjudicated Category 1 or Category 2 event, the NYHA/ROSS class change, and the PGIS change; and the time-to-event will be analyzed using a Cox proportional hazard model, stratified by age group with treatment (sacubitril/valsartan, enalapril) included as a fixed-effect factor. The NYHA/ROSS class change and the PGIS change will be analyzed using a longitudinal proportional cumulative odds model with age group, baseline class, treatment (sacubitril/valsartan, enalapril), visit, treatment-by-visit interaction included as fixed-effect factors; and patient-specific intercepts included as random effects.

The sample size and power calculation is based on the data from the Carvedilol pediatric HF study10 within the subgroup of patients with heart failure due to systemic left ventricle systolic dysfunction, whereby for patients receiving sacubitril/valsartan and enalapril, the distribution of patients in the five categories were projected based on the observed distribution in the carvedilol pediatric HF study (further details available in Supplementary appendix IV).10 It is assumed that the additional treatment effect

from the tie-breakers within each category is similar to that of the five-category response, and that 50% of the between-treatment-group ties can be resolved. The sample size of 360 will provide approximately 80% power for the primary test accommodating for the interim analysis.

The trial is designed to maintain at least 80% power assuming a type 1 error rate of 0.05 (two-sided) for the global rank endpoint. The global rank endpoint differentiates between the two treatment groups by comparing the rank order of the patients in the two treatment groups. Patients who are tied comparing the two treatment groups reduce the discriminatory ability of the global rank endpoint. In order to maintain 80% power for the primary global rank endpoint, there will be a blinded assessment of the proportion of ties in the primary endpoint approximately six months prior to conclusion of the study. The sample size may be increased in order to maintain 80% power.

Study completion/Interim analysis

After 360 patients have completed the study and at least 80 patients have had an event in Category 1 or 2, Part 2 of the study will be stopped. An interim efficacy and futility analysis is planned when at least 50% of the patients (and at least 36 patients from each age group) have completed the study, and at least 40 patients have had an adjudicated event in Category 1 or 2. The O'Brien-Fleming boundary will be used for the efficacy interim analysis. Safety monitoring will be carried out approximately every 6 months. The trial may only be concluded early for efficacy if a significant difference between the two treatment arms for the primary efficacy endpoint is achieved by crossing the pre-specified boundary at the interim analysis.

Discussion

The benefits of sacubitril/valsartan versus standard of care (ACEI) reported in the landmark PARADIGM-HF trial,12 and the evidence that pediatric HF with systemic left ventricular systolic

dysfunction shares a similar pathophysiologic basis with adult HFrEF involving neurohormonal systems,15' 20 provide a strong rationale for the PANORAMA-HF trial.

Unlike adult HFrEF, pediatric HF is more heterogeneous and has different etiologies. Therefore, tailored studies for pediatric HF treatment are needed. In the Carvedilol Pediatric HF study, which used a clinical endpoint similar to this study, a potential treatment benefit was observed in the subgroup of patients with systemic left ventricle morphology.10 When underlying ventricular morphology was taken into account in the carvedilol Pediatric HF study, a significant interaction was seen between treatment and ventricular morphology (p=0.02) indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a morphologic left ventricle (non-beneficial trend).10 Furthermore, numerous small observational studies in children 1.5 days to < 18 years old have suggested that ACEI benefits patients with HF caused by systemic ventricular systolic dysfunction, left to right shunt, congenital heart disease, and valvular regurgitation.14' 26' 41 However, studies examining the use of ACEIs and ARBs in infants with single-ventricle physiology and adults with systemic right ventricle failed to show significant benefit.7' 42-44

In view of (1) a potential differential effect that systemic ventricular morphology may have on outcomes (based on the carvedilol Pediatric HF study) and (2) studies in children suggesting benefit from ACEI in HF due to systemic left ventricular systolic dysfunction but no benefit from ACEI or ARB treatment in HF due to single ventricle or systemic right ventricle anatomy/physiology,4' 7' 26' 42-48 this study will examine a more homogeneous population with biventricular heart physiology and HF due to systemic left ventricle with reduced EF. Such an approach will result in a patient population that resembles more closely the adult HF population in which sacubitril/valsartan has been shown to be more effective than enalapril in reducing mortality and HF hospitalization, and improving symptoms in patients with HF.12

A concern with the selected population, based on preclinical rat toxicity studies, is that the use of a RAAS blocker may affect fetal kidney development. Therefore, children < 1 month old (full term infant or < 44

weeks post conception for pre-term infants) are excluded from the study. Thus, the study population will comprise children aged from 1 month (or > 44 weeks post conception for pre-term infants) to < 18 years old.

We believe this seamless, two-stage (Phase II/Phase III) trial represents an innovative approach to pediatric HF clinical study design. Part 1 will investigate the PK/PD and Part 2 the efficacy of sacubitril/valsartan in pediatric HF patients. The first stage is designed for dose selection, whereas the second stage aims to establish the efficacy of the selected dose compared with a common standard care of therapy, the ACEI enalapril. Drug development processes are traditionally separated into distinct, independent, and sequential clinical development phases. However, this approach can cause a delay in new therapeutics reaching clinical practice.49 Adaptive design studies have been used in recent trials as a way to shorten clinical development timelines. A survey in 2012 showed a considerable increase in the use of adaptive designs, which hold the potential to improve the drug development process through reduced time and effective resource use. 50 Furthermore, these prospectively planned studies are geared towards enhancing the efficiency, validity, and integrity of the study. Such two stage study designs are now commonly considered in pharmaceutical research and development as a means to efficiently identify an appropriate patient population and thereby reduce the required population size. 51, 52

This study is designed to determine if sacubitril/valsartan improves clinical outcome and symptoms.

Answering this important question and providing data that informs clinical use requires an adequately

powered clinical study. A study with a primary endpoint based on clinical cardiovascular events alone

would require a sample size much larger than is feasible with pediatric HF. There are many obstacles to

performance of pediatric HF studies and these include: complexities of pediatric drug formulation, dose

selection, heterogeneous etiologies of HF, comorbid conditions, inexperienced pediatric clinical sites, and

small number of patients eligible for the study. In addition, biomarker endpoints such as left ventricular

function and BNP are not adequate surrogate endpoints for health authority approval for a new

cardiovascular drug indication. Therefore, we have developed a global rank endpoint for the primary

endpoint of this study that combines clinical events with clinical reported physical function and patient reported symptoms. This ambitious, adaptive-design, seamless study of sacubitril/valsartan for pediatric HF is expected to be the largest prospective pediatric HF trial attempted to date and is the first to use a global rank endpoint. The successful completion of the PANORAMA-HF study will inform and facilitate future studies in pediatric HF.

Study design of sacubitril/valsartan in Pediatric Heart Failure Figure Legends

Figure 1: Design of the two-stage, seamless, adaptive PANORAMA-HF study assessing the PK/PD, safety, and efficacy of sacubitril/valsartan versus enalapril in pediatric heart failure patients with systemic left ventricle and reduced left ventricular systolic function

bid, twice-weekly; m, month; mg, milligram; kg, kilogram; PD, pharmacodynamics; PK, pharmacokinetics

Figure 2: Global rank endpoint for patients without category 1 or 2 clinical events

Patients with category 3, 4 and 5 events will be ranked according to the change from baseline for (A) clinician reported functional capacity and (B) patient reported HF symptoms. Patients tied in rank based on A and B will have ties broken by the PedsQL Physical Functioning domain.

ClinRO, clinical reported outcome assessments; HF, heart failure; NHA, New York Heart Association; PedsQL, Pediatric Quality of Life Inventory; PGIS, Patient Global Impression of Severity; Phys Funct, Physical Functioning; PRO, patient reported outcome assessments; Sx, symptoms; Txp, transplant

Study design of sacubitril/valsartan in Pediatric Heart Failure Acknowledgments

The study is solely funded by Novartis Pharmaceuticals Corporation, USA. The authors are solely responsible for the design and conduct of the study, all study analyses, the drafting and editing of the paper and its final contents.

The authors would like to thank Paul Coyle, Shuja Jacob, and Sreedevi Boggarapu (employees of Novartis) for providing writing/editorial assistance. All authors reviewed and critically revised the manuscript for content and approved the final version of the manuscript for submission.

Disclosures

RS, CC, NH, LK, JR, DB, PK, and MB are consultants of Novartis. FC, CB and ZZ are employees of Novartis Pharmaceuticals Corporation. RS, NH and LK received grants/research support from NIH/NHLBI. LK is a board member of Pediatric Cardiac Care Consortium.

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sacubitril/valsartan PK/PD

0.8 mg/kg

- ----y

sacubitril/valsartan bid N = 180

enalapril bid N = 180

T^f I I I I I I I I n7^

Visit 1 101 1102* | 103to 199 2011202'| 203to 299 301 401 402 403 404** 405 406 407 411 412 413 414 415 416/499 120" 220**

Time (weeks) .-3 .0 2 4 6 8 12 16 32 36 40 44 48 52

"►P Epoch Screening

First PK dose

Period 2 Second PK dose Screening

PreRandomization

Double-blind epoch

*Open label enalapril visits "Optional visit

Figure 1

Hypothesis PRO/ClinRo PRO/ClinRo

Concept Instruments

Figure 2

Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study) Academic research paper on "Clinical medicine"

Abstract of research paper on Clinical medicine, author of scientific article — Robert Shaddy, Charles Canter, Nancy Halnon, Lazaros Kochilas, Joseph Rossano, et al.

Similar topics of scientific paper in Clinical medicine , author of scholarly article — Robert Shaddy, Charles Canter, Nancy Halnon, Lazaros Kochilas, Joseph Rossano, et al.

Academic research paper on topic "Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study)"