key: cord-302690-0v7ne7vi
authors: Chow, Clara K.; Atkins, Emily R.; Billot, Laurent; Chalmers, John; Hillis, Graham S.; Hay, Peter; Neal, Bruce; Nelson, Mark; Patel, Anushka; Reid, Christopher M.; Schlaich, Markus; Usherwood, Tim; Webster, Ruth; Rodgers, Anthony
title: Ultra-low-dose quadruple combination blood pressure lowering therapy in patients with hypertension: The QUARTET randomized controlled trial protocol()
date: 2020-10-02
journal: Am Heart J
DOI: 10.1016/j.ahj.2020.09.017
sha: 
doc_id: 302690
cord_uid: 0v7ne7vi

High blood pressure is the leading cause of preventable morbidity and mortality globally. Many patients remain on single-drug treatment with poor control although guidelines recognize that most require combination therapy for blood pressure control. Our hypothesis is that a single-pill combination of four blood pressure- lowering agents each at a quarter dose may provide a simple, safe and effective blood pressure lowering solution which may also improve long term-adherence. The QUARTET (Quadruple UltrA-low-dose tReaTment for hypErTension) double-blind, active controlled, randomized clinical trial will examine whether ultra-low-dose quadruple combination therapy is more effective than guideline recommended standard care, in lowering blood pressure. QUARTET will enroll 650 participants with high blood pressure, either on no treatment or on monotherapy. Participants will be randomized 1:1 and allocated to intervention therapy of a single pill (quadpill) containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg and bisoprolol 2.5 mg or to control therapy of a single identical appearing pill containing irbesartan 150 mg. In both arms step up therapy of open-label amlodipine 5 mg will be provided if BP is >140/90 at 6 weeks. The primary outcome is the difference between groups in the change from baseline in mean unattended automated office systolic blood pressure at 12 weeks follow-up. The primary outcome and some secondary outcomes will be assessed at 12 weeks, there is an optional 12 months extension phase to assess longer term efficacy and tolerability. Our secondary aims are to assess if this approach is safe, has fewer adverse effects and better tolerability compared to standard care control. QUARTET will therefore provide evidence for the effectiveness and safety of a new paradigm in the management of high blood pressure.

Burden of high blood pressure and treatment gaps 84 High blood pressure is the leading cause of preventable morbidity and mortality globally. 1 The benefits of blood 85 pressure lowering in reducing cardiovascular events are unequivocal 2 and there is clear evidence of greater benefits 86 for combination-based therapy compared to monotherapy. 3 Furthermore, numerous studies have indicated the 87 benefits of more rapid control of blood pressure, and have shown that this is more likely to occur with use of 88 combination therapy. 4 Yet, control of high blood pressure is poor, with only 1 in 3 on treatment achieving blood 89 pressure targets. 5-8 90

Previous guidelines typically recommended initiating monotherapy, up-titration of dose, switching drugs if not 91 tolerated, and adding other agents if needed. 7 This often takes multiple visits to achieve target blood pressure -and 92 studies show that most individuals remain on monotherapy and with inadequate blood pressure control. 5 The largest 93 global survey of hypertension practice showed only 34% of those treated for high blood pressure were controlled 94 (SBP<140 and DBP<90mmHg), and 31% of treated patients were receiving combination therapy. 5 The 2017 May 95

Measurement Month blood pressure screening campaign included a convenience sample of 1.2 million across 34 96 countries, and found 54% of those treated had adequate blood pressure control. A 2013 survey of 31 international 97 hypertension guidelines showed that 27 (87%) now recommend use of combination for initial treatment, but typically 98 only as an option for patients at >20/10mmHg from goal. 9 As 50 to 75% of patients require combination treatment for 99 blood pressure control, there has been increasing interest in the initial use of combination therapy. 10 Most recently 100 the ESC/ESH guidelines recommended initial combination therapy for most people, except those with low 101 cardiovascular risk and SBP<150mmHg and frail older adults. 11 102

There are multiple barriers to blood pressure control that are patient, healthcare system and physician related. 103 Patient adherence is a major factor and is worsened by increased number of medications, complexity of dosing 104 regimens and medication side effects. 12, 13 'Therapeutic inertia', the reluctance of physicians to treat mild 105 hypertension and up-titrate medications, is also a barrier to blood pressure control. A large study conducted in 106

Western Europe and the US of more than 20,000 people with hypertension found that blood pressure control rates 107 ranged from 31 to 63%, and only 15 to 38% of instances of elevated blood pressure had up-titration during the visit. 14 108

There is a clear need for improved strategies that will: a) make the treatment of high blood pressure more effective 109 and easier to implement for doctors and patients; b) quickly and safely bring blood pressure under control and; c) 110

increase long term adherence with therapy. We hypothesize that a single-pill combination of four blood pressure 111 lowering agents at quarter dose may achieve these goals. 112

Rationale for very low-dose combination therapy 113 Dose response data on blood pressure reduction 114 Pharmacological dose response curves for blood pressure lowering drugs indicate that a quarter-dose has at least half 115 the blood pressure-lowering effect of a standard dose (usual maintenance dose) but with much fewer side effects.

A systematic review of all randomized trials of quarter dose blood pressure lowering identified a total of 42 trials, 38 117 of single quarter-dose comparisons, seven of dual quarter-dose comparisons and two of a quadruple quarter-dose 118 combination. 15 Compared to placebo, single quarter dose therapy reduced blood pressure by 5/2 mmHg (p<0.0001) 119

with no increase in adverse events. Dual quarter-dose therapy was similarly efficacious as standard-dose 120 monotherapy. Two studies of quadruple quarter-dose therapy have been published. One unblinded pilot with four 121 control groups of standard-dose monotherapies of the components showed a reduction of 13/8mmHg compared to 122 the average reduction of all four controls after four weeks. 16 The other, our pilot, a double-blinded placebo-controlled 123 cross-over trial in people with newly diagnosed hypertension showed a reduction of 22/13mmHg after four weeks 124 active treatment versus placebo. 17 125

There is strong evidence that the blood pressure lowering effects of different classes of drugs are independent and 126 fully additive. 15, 18 The effects of adding a second blood pressure lowering agent are closely concordant with those 127 predicted by independent effects, occur across all pairs of medication classes, and are about five times more effective 128 than doubling the dose of the first agent. 18 The additive effects across three classes of low-dose drugs were also 129 J o u r n a l P r e -p r o o f demonstrated in a placebo-controlled, crossover trial of three half-dose blood pressure drugs in 86 participants aged 130 over 50 years without a history of cardiovascular disease. 19 Overall a 17.4/9.4 mmHg blood pressure reduction was 131 observed, compared to the anticipated 17.9/9.5 mmHg decline expected from the cumulative effects of the three 132 separate agents. 133

Dose response data on adverse effects Biochemical changes appear minimal with quarter-dose therapy compared to standard-dose monotherapy. 15 These 149 data suggest that dose-dependent adverse effects will be minimal with this intervention, and idiosyncratic reactions 150 are uncommon with these component medications. 151

Objective 152

The primary objective of the Quadruple UltrA-low-dose tReatment for hypErTension (QUARTET) trial is to examine 153 whether ultra-low-dose quadruple combination therapy (quadpill) is more effective than guideline recommended 154 therapy with an ARB plus a CCB if required in lowering blood pressure. Our secondary aim is to assess if this approach 155

is safe and has fewer adverse effects compared to standard care. 156

Trial design 158 This is a 12-week double blind randomized controlled trial of 650 patients with high blood pressure. Participants are 159 randomized in a 1:1 allocation ratio using a central computer-based service, to initial therapy with quadpill or to a 160 standard dose of an ARB, with a CCB added as required, as per current guideline recommendations ( Figure 1 ). The 161 primary outcome is reduction in mean office systolic blood pressure (SBP) measured using Omron HEM-907 at 12 162 weeks. Secondary outcomes include: the proportion of participants with controlled blood pressure (SBP<140mmHg 163

and diastolic blood pressure [DBP] <90mmHg) at 6 weeks and 12 weeks, ambulatory blood pressure (ABP) measures at 164 12 weeks, tolerability and the occurrence of adverse events. Learnings from the quadpill pilot informed the design and 165 conduct of the present trial. 17 166

Extension study 167 An extension study to 12 months follow-up involves two more visits, at 26 and 52 weeks after randomization to 168 examine longer term efficacy and tolerability. 169 Setting, locations and recruitment 231

Participants are recruited from community general practices and outpatient clinics. Current active sites are listed in 232 the appendix. There is a total of 10 sites in 4 of the 8 states and territories of Australia (New South Wales, Victoria, 233

Tasmania and Western Australia), with 3 of these based in primary care and the rest in hospital or university locations. 234 We employ several methods to identify potentially eligible participants. This includes community advertising and 235 awareness campaigns (using print and electronic media advertisements and radio), referral by clinicians aware of the 236 study ( hydrochlorothiazide is included in a number of fixed dose combinations, some recent guidelines 23 and literature 249 recommend indapamide or chlorthalidone, principally on the basis that some data suggest more cardiovascular event 250 reduction with these agents, 24, 25 though a recent paper suggests no difference. 26 The additional blood pressure 251 reduction expected from including a quarter-dose of a different class of drug is about three times as great as would be 252 achieved by doubling the dose of any other component. 15 We chose the 4 th agent to be a BB, due to its long duration 253 of action, relatively minimal side effects at a quarter dose. The choice of a beta-blocker as a 4 th agent of choice is also 254 consistent with a number of international hypertension guidelines which specify Beta-blocker use after renin 255

angiotensin system blockers, CCBs and thiazide type diuretics. 22, 27, 28 We chose bisoprolol over atenolol due to its 256 longer duration of action. The other major consideration was use of off-patent components to minimize costs. 257

The control group follows the recommendations of the current Australian guidelines, 22, 29 i.e. initiating with an ACE-I or 258

ARB, and if blood pressure is not controlled adding a CCB. This approach is also consistent with the 2011 NICE 259

Hypertension Guidelines, and among the preferred treatment options in the 2013 JNC-8 Guidelines and the 2013 260 ESC/ESH Guidelines, which were current at the inception of this study. 23, 30, 31 We chose irbesartan as it is the most 261 commonly prescribed ARB in Australia and amlodipine because it is the most commonly prescribed CCB. 262

Patients who are on monotherapy at time of recruitment will be asked to stop their treatment while they are taking 263 the study treatment. The drug is provided to both intervention and control arms at no cost to the participant. 264

Medications are provided in quantities of 99 tablets at 3 monthly intervals. That is a medication kit is given to patients 265 at baseline, week 12 and at 6 months and 9 months in participants participating in the extension study. Each kit 266

consists During the study we will obtain information on self-reported health service utilization, and specifically ask if patients 295 have seen and how frequently they have seen the following health providers -Practice nurse, General Practitioner, 296

Doctor in public hospital emergency department (not admitted), Doctor in public outpatients clinic for any reason and 297

Doctor in private specialist clinic for any reason. We also request consent to link data to MBS (Medical Benefits 298

Schedule -listing of Medicare services subsidized by the Australian Government) and PBS (Pharmaceutical Benefits 299

Scheme -listing of medicines subsidised by the Australian Government). 300

Information is collected on serious adverse events and adverse events of special interest (see list in appendix). We 301 specifically query participants about adverse events of special interest at each visit (6 week, 12 weeks and additional 302 visits for extension participants 6 months and 12 months). Adverse events of special interest include: dizziness, 303 hypotension, pedal oedema, muscle cramps, bradycardia, heart failure, hypersensitivity reactions (skin rashes, itching), 304

gastrointestinal complaints (nausea, vomiting, diarrhea), musculoskeletal complaints, headaches. Adverse events are 305 not adjudicated. The EuroQol Group (EQ-5D-3L) Quality of Life questionnaire is completed by participants at their 306 baseline, 12 week and final visits. 307 308 Outcome measures and outcome assessment 309 The primary and secondary outcomes are listed in Table 1 . 310

The blood pressure measurements are recorded using an Omron HEM907. An appropriate cuff size is selected for all 311 BP measurements. First a measure of clinic blood pressure is observed and recorded by research staff. Then, 312

automated office blood pressure is measured following the recommendations of the European Society of 313

Hypertension/European Society of Cardiology and Australian National Heart Foundation. 22, 30 This requires the 314 research staff to set the automated device to take three separate BP measurements while the researcher steps out of 315 the room (unattended BP measurement). The Omron HEM907 is programmed to start the first measurement after 316 five minutes of rest, then at one-minute intervals. The primary outcome "mean SBP" will be calculated using the 317 J o u r n a l P r e -p r o o f average of these three unattended measures. In addition, 24-hour ABPM is conducted at baseline, 12 and 52 week 318 follow-up visits using a Suntech Oscar-2 programmed to measure every 30 minutes while participant is awake, and 319 hourly during sleep. 32, 33 320

Sample size 321 A sample size of 650 patients provides 90% power at p=0.05 to detect a difference between randomized groups of 4 322 mmHg in the primary outcome, assuming a standard deviation (SD) of 15mmHg. 34 A sample of 650 also has 85% 323 power to detect a 3mmHg difference in average 24hr SBP (SD 12 mmHg) 34 and 85% power to detect a 25% increase in 324 the proportion with controlled blood pressure assuming 50% are controlled in the comparator group. All calculations 325 allow for a 10% dropout or data loss rate. It is assumed that irbesartan 150 mg and up-titration with the addition of 326 amlodipine in 75% of participants in the control group will give an average reduction of 12mmHg from an average 327 baseline SBP of 150mmHg. 35 Based on the information presented in the background, quadruple combination therapy 328 will reduce SBP by at least 16mmHg. 16, 20 329

The rate of all adverse events is predicted to be around 15% in the control group, 35 and this study will have 90% power 330

to rule out an increase of 5 percentage points (i.e. a non-inferiority margin of 20%) assuming the true incidence of 331 adverse events in the quadpill group is 10% and a one-sided test with alpha=2.5%. The 10% incidence of adverse 332 events is a conservative estimate from adding up the incidence of side effects from each treatment class at ½ standard 333 dose described in a previous systematic review: BB 5.5%, TZ 2.0%, CCB 1.6% and ARB 0%.

Interim analyses, monitoring, and stopping guidelines 335

The trial data safety and monitoring committee (DSMC) monitors safety data on an ongoing basis, with the analyses 336 performed by an independent statistician from the George Institute for Global Health. The DSMC can recommend the 337

Steering Committee of the QUARTET Study should continue the study unchanged, adjust the duration of follow-up, or 338 terminate the study early if there is clear and substantial evidence of benefit, if the data suggests the risk of adverse 339 events substantially outweighs the potential benefits, or for futility. The first DSMC meeting was held after 25% of 340 participants completed 12 weeks follow up and recommended continuation of the study without modification. 341

The unblinded statistician prepared a computer-generated randomization schedule stratified by site and using 343 permuted blocks of variable size. This was loaded into the web-based data management system (IBM Clinical 344 Development, Morrisville USA). Allocation concealment is maintained as only the unblinded statistician and unblinded 345 data manager have access to the randomization list and allocation within the database. 346

Participants are enrolled at sites by blinded staff, with participant randomization and study drug allocation conducted 347 through the database with blinding maintained. The study drug kit numbering is separate to the randomization 348 sequence to prevent the kit allocation potentially unblinding site staff. The investigators, project management, site 349 staff, and participants are blinded to the randomization sequence and treatment allocation. 350

The main analyses of study outcomes will be conducted according to the principle of intention-to-treat. The primary 352 analysis of change in SBP at 12 weeks will be performed using an analysis of covariance including the treatment arm 353 and baseline SBP as a covariate. Continuous secondary outcomes will be analyzed similarly. Additional analyses will 354 include all follow-up measurements in a longitudinal model including treatment arm, visit, and a treatment by visit 355 interaction term as well as the baseline measurement. Within-patient correlations will be modelled using generalized 356 estimating equations or random effects. A similar approach will be applied to binary endpoints (e.g. blood pressure 357 control) with log-binomial regression used in place of linear regression. A per-protocol analysis will be performed to 358 provide information on the difference in efficacy between the two study treatments. There will also be pre-defined 359 subgroup analyses, including by baseline blood pressure, gender, age, diabetes, education and by BP lowering 360 treatment at baseline (no treatment versus monotherapy). A detailed analysis plan will be finalized prior to unblinding. Cost-effectiveness and cost-utility analysis 364 An incremental cost-effectiveness analysis will be used to compare the costs and outcomes of the treatment arms 365 from a health system perspective. This will consider the cost per mmHg reduction in systolic blood pressure and the 366 cost per quality adjusted life-year gained for quadpill versus monotherapy to facilitate comparison with other 367

interventions. Costs will be determined through the collection of resource use during the study period and estimates 368 of commercial costs for the quadpill. Information on hospital admissions, doctors' visits and medications is collected at 369 follow-up visits. 370

A semi-quantitative survey and in-depth interviews will be conducted to assess the acceptability of quadpill, and to 372 identify which factors are important to participants and health providers in blood pressure reduction. Patient 373 acceptability is a critical component of healthcare innovation. Patients and health providers in the study will be invited 374

to answer questions assessing their perceptions, experience and the degree of engagement with the intervention at 375 the completion of the trial. Patients and health providers will be invited to participate in semi-structured interviews on 376

perceptions of the utility and acceptability of the intervention program. Examples of questions are included in the 377 appendix. Interviews will be recorded and transcribed, then coded using NVivo. From the coded data key themes will 378 be identified. 379

Trial management, funding, and sponsorship

The trial conduct is overseen by a steering committee (list in Appendix). The central coordinating center ensures 381

implementation of the study according to the protocol, timelines and recruitment targets. We use an electronic data 382 management system incorporating study checks and omissions. An independent data and safety monitoring 383 committee meets regularly to assess emerging evidence on safety and efficacy. The QUARTET trial is the first large-scale trial to examine a quadruple, quarter-dose regimen. This approach has many 406 theoretical benefits, including greater efficacy and fewer side effects as well as pragmatic benefits that should 407 improve adherence and decrease costs. If this new intervention achieves its conservative additional 4mmHg of blood 408 J o u r n a l P r e -p r o o f pressure reduction compared to that conferred by optimal guideline-recommended care, such a difference could 409 translate into an additional 15 to 20% reduction in cardiovascular events. 3 

There has been increasing acceptance of the role of dual anti-hypertensive combinations in blood pressure 411 management both due to the observation that most patients require more than one agent to achieve BP control, and 412 by trials showing early use of combination is beneficial. The TRIUMPH trial evaluated a half-strength triple pill, but with several points of difference, most importantly the 426 comparison against a variety of usual care options in Sri Lankan outpatient hospital care, with a focus on improving 427 the access and affordability of blood pressure lowering medications in this setting. 44 This study found 70% of 428 participants in the triple pill group achieved their target blood pressure versus 55% in the usual care group, 44 and the 429 triple pill was cost-effective compared to usual care. 45 The Quadpill Pilot trial was a placebo-controlled pilot study was 430 conducted in treatment-naïve people with newly diagnosed high blood pressure in primary care. 17 The ultra-low dose 431 quadruple combination was very effective at lowering blood pressure in the short-term single center pilot study, 432

hence the current study is needed. A sister trial, QUARTET USA (Clinicaltrials.gov NCT03640312), is currently underway 433

in Chicago USA and an individual patient data meta-analysis is planned once both trials are completed. 434

If the intervention tested here is proven to be safe and effective, the trial results could be rapidly implemented, with 436 immediate benefits in routine clinical practice. Similar therapy could be provided to patients using available 437 medications, including existing dual combinations and the use of dose administration aids. Ultimately, most advantage 438 will be gained from single pill formulations. The results of the current trial would stimulate the development of such 439 products if the results were favorable. 440

In summary, ultra-low-dose combination therapy has the potential to have a major impact on current poor rates of 441 blood pressure control globally. The critical next step is direct evidence on effectiveness and safety in a large-scale 442 randomized controlled trial, which the QUARTET trial aims to provide. 443

Authors' contributions 444 CKC wrote the first draft of the Quartet protocol that was subsequently funded by NHMRC with critical review from 445 AR as the senior author and all CIs of the NHMRC protocol including GH, MS, TU, RW, LB. ERA has been the 446 postdoctoral fellow on Quartet, prepared the first draft of the manuscript and revised the manuscript. All authors 447

have reviewed the final manuscript. We also acknowledge Henry Krum (deceased) who provided critical review of the 448

Quartet protocol submitted to NHMRC. 449

The QUARTET trial received principal funding through a project grant from the National Health and Medical Research 451

Council Australia (APP1100377). The trail was also supported by funding from NHMRC program grants (APP1052555 452 and APP1092642). Individual investigators also received support to enable their time allocation to the trial: CC was 453 J o u r n a l P r e -p r o o f supported by NHMRC Career Development Fellowship Level 2 (APP1105447), ERA was supported by a National J o u r n a l P r e -p r o o f Table   TABLE 1 

Difference between groups in change in mean office systolic blood pressure from baseline to 12 weeks Secondary outcomes 24-hour ambulatory blood pressure a) Difference between groups in mean 24-hour SBP and DBP at 12 and 52 weeks b) Difference between groups in mean change in 24-hour SBP and DBP from 0 to 12 weeks, 0 to 52 weeks and 12 to 52 weeks c) Difference between groups in mean daytime SBP and DBP at 12 and 52 weeks d) Difference between groups in mean night-time SBP and DBP at 12 and 52 weeks e) Difference between groups in daytime, night-time, and 24-hour BP load (percentage area under the blood pressure curve above normal day, night, and 24-hour values as per National Heart Foundation guidelines f) Difference between groups in the proportion of non-dippers (night-time BP is not more than 10% lower than average daytime BP as per National Heart Foundation guidelines) and coefficient of variability of BP 33 Other blood pressure measures a) Difference between groups in mean automated office systolic (52 weeks) and diastolic blood pressure (12 and 52 weeks). b) Difference between groups in standard clinic SBP/ DBP at 12 and 52 weeks c) Hypertension control (% with SBP <140 mmHg and DBP <90 mmHg) at 6, 12, 26 and 52 weeks, d) Percentage requiring step-up treatment at 6 weeks e) Percentage requiring step-up blood pressure lowering treatment over 52 weeks f) Percentage with both BP control (as defined above) and no adverse events. g) Difference between groups in SBP and DBP variability Tolerability a) Difference between groups in potentially related side-effects (dizziness, blurred vision, syncope/ collapse/ fall, chest pain/ angina, shortness of breath, cough, wheeze, ankle edema, skin rash, itching, gout, hyperkalemia, hypokalemia, hyponatremia, other) b) Difference between groups in mean potassium, uric acid, blood glucose, cholesterol and fractions, ALT, AST, UACR (Urine albuminto-creatinine ratio) and creatinine levels. c) Difference between groups in participant withdrawals from treatment Safety

Percentage with any severe adverse event Medication adherence Self-reported measures and pill counts

The ratio of the difference in costs and outcomes between treatment arms Patient and prescriber acceptability End of study feedback questionnaires Note: Key secondary outcomes have been put in bold J o u r n a l P r e -p r o o f A Suspected Unexpected Serious Adverse Reaction is any UAR that at any dose meets the definition of an SAE (refer to section 3). Any event that meets the definition of a SUSAR between when the informed consent form is signed and the end of study visit at week 12 or week 52 will be reported to the local HREC/ IRB and the relevant regulatory authorities as per local requirements and ICH Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.

Examples of questions asked of providers and participants to assess acceptability of the quadpill intervention Examples of questions asked of participants include:

-During the trial, how easy did the participant find it to take the trial medications? -If the LDQT is available to be prescribed by participant's usual doctor, how likely would the participant be to request it? -Are there any other comments the participant had about the LDQT?

Examples of questions addressed to healthcare providers about the quad pill include:

-What do you think are the potential benefits of LDQT or your concerns about LDQT? -If LDQT was available, in what circumstances would you prescribe it or what evidence would you require to start prescribing LDQT? -What do you consider to be important factors in patients' decisions to take blood-pressure lowering medications?

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J o u r n a l P r e -p r o o f Harms All serious adverse events (SAEs) and adverse events of special interest (AESI) experienced by a participant after the informed consent document is signed and until the end of the study at week 12 or 52 will be collected and reported to the CCC as per applicable ICH GCP and applicable regulatory guidelines. If an SAE is unresolved at the conclusion of the study, a clinical assessment will be made by the medical monitor as to whether continued follow up of the SAE is warranted. SAE criteria, definitions and guidance for reporting are outlined in section 1 to 4

An adverse event is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product at any dose that does not necessarily have to have a causal relationship with this treatment. Therefore, an AE can be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product. This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing conditions.

The expected adverse reactions to the BP lowering medications that will be used in QUARTET are well known (Appendix 2). To better assess participants' tolerability to the study medications the following AESI's and whether they are new or ongoing from baseline will be reported to the CCC regardless of severity and seriousness: 

A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose:  results in death  is life threatening in the opinion of the attending clinician (i.e. the patient was at risk of death at the time of the event; it does not refer to an event that might hypothetically have caused death had it been more severe)  requires inpatient hospitalisation or prolongation of existing hospitalisation (Any hospitalisation that was planned prior to randomisation will not meet SAE criteria. Any hospitalisation that is planned post randomisation will meet the SAE criteria)  results in persistent or significant disability or incapacity  results in congenital anomaly or birth defect (Note that the females in the study population are likely to be postmenopausal)  is an important medical event in the opinion of the attending clinician that is not immediately life-threatening and does not result in death or hospitalisation but which may jeopardise the patient or may require intervention to prevent one of the other outcomes listed above An adverse event that meets the above categories between when the informed consent form is signed, the end of study visit at week 12 or at 26 and 52 weeks if patient is participating in the study extension and until the 28 days after the study drug discontinued will be reported as an SAE. All SAEs are required to be reported to the sponsor team within 24 hours of the study team first becoming aware of the event. The SAE will also be required to be reported to the relevant HREC/ IRBs within the timeframe specified in the relevant committee guidelines. If irbesartan or the LDQT is discontinued as a result of an AE, the study team will document all events leading to the discontinuation of treatment. Adverse events which do not fall into these categories are defined as non-serious.

An unexpected adverse reaction (UAR) is an adverse reaction, the nature or severity of which is not consistent with the applicable product information. Refer to (Quartet protocol, Appendix 2) for a list of expected adverse reactions for the interventions used in this protocol.J o u r n a l P r e -p r o o f