The Precision HYpertenSIon Care (PHYSIC) study: a double-blind, randomized, repeated cross-over study

Figures & data

Figure 1. Study design. Each patient is randomly assigned to a treatment sequence created from one of the six possible combinations, by random permutation of the order in which the active treatments are given (the figure is a mere illustration of a few examples of possible sequences). Hence, 1/6 of the patients receive ACEi and ARB in two periods each, 1/6 of patients repeat the ACEi and CCB periods, 1/6 of the patients repeat the ACEi and Diuretic periods, 1/6 repeat the ARB and CCB periods, 1/6 repeat the ARB and Diuretic periods, and 1/6 repeat the CCB and Diuretic periods. Block randomization is used to ensure that approximately the same number of patients are assigned to each of the six combinations of active treatments. ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; Diuretic = thiazide diuretic. Blank arrows indicate placebo run-in and wash-out.

Table 1. Study outline.

Setting	Patients diagnosed with hypertension with a systolic blood pressure between 140 and 159 mmHg within five years before the start of the trial. Patients must be pharmacologically untreated or use blood pressure-lowering monotherapy at the time of recruitment to the present study.
Design	Double-blind, randomized, repeated cross-over, single-centre study.
Number of patients (planned)	300 patients included to obtain 240 evaluable patients.
Interventions	Candesartan: 8 mg weeks 1–2; 16 mg weeks 3–8 Lisinopril: 10 mg weeks 1–2; 20 mg weeks 3–8 Amlodipine: 5 mg weeks 1–2; 10 mg weeks 3–8 Hydrochlorothiazide: 12.5 mg weeks 1–2; 25 mg weeks 3–8.
Treatment duration	The study consists of six active treatment periods: four classes of blood pressure-lowering drugs will be tested, treatment with two classes are repeated for each patient. Patients will be assigned a treatment order based on block randomization ensuring that the same number of patients will repeat each treatment. Active drug is given during 6–8 weeks of each treatment period (titration dose week 1–2, target dose week 3–8). Placebo will be administered during 2 weeks of placebo run-in (between visit 1 and 2) and during 7 days’ wash-out between treatment periods. This gives a total duration of treatment of 47–59 weeks for each included patient.
Outcome	The primary analysis of individual variation in treatment differences in visit 4 daytime (10.00–20.00) ambulatory systolic blood pressure will be performed using a random effects model with correlated random intercept and treatment contrasts, allowing correlation between all random effects, and with treatment period as a fixed effect. All available periods with >90% treatment adherence from all randomized patients will be used.

Table 2. Sequence of events.

Visit	1	Placebo run-in (≥2 weeks)	2	Treatment period			5
				Dosing at home	3	4
Week	–1 –(–2)		1	1–7	7	8
Day	–7 –(–14)		1	2–54	55	56
Informed consent	✓
Inclusion/exclusion criteria	✓		✓
Anthropometry^a	✓
Physical examination	✓
Office BP^b	✓		✓		✓
Concomitant medication	✓		✓		✓
Safety samples^c	✓		✓		✓^d
DNA genomic samplese	✓
Medical history Q^g	✓
Beliefs about medicine Q	✓
Placebo dosing		✓					✓
Randomization			✓
Study drug dosing^h			✓	✓	✓	✓
Staff train patients in electronic diary^f			✓
Self-reporting of symptoms in electronic diary^i				✓	✓
PERSYVE Q			✓		✓
Pulse wave analysis			✓
Capillary blood sampling and dried blood spots			✓
Venous blood samples for DNA methylation, RNA, other biomarkers^j			✓		✓
AE/SAE recording^k			✓		✓^q
Treatment preference rating Q^l					✓
24-h BP/ECG^m			✓^n		✓	✓
Return of unused study drug by patients					✓
Supply next study drug and 7-day placebo					✓
Overall treatment preference rating^o							✓
Prescription of preferred drug for continuous use^o							✓

^a Measured using standard field protocols.

^b Prior to measurement patient will rest sitting for 10 min. Measurement twice within 5 min in-between measurements using a sphygmomanometer.

^c The following safety samples will be analysed: Hb, HbA1c, sodium, potassium, calcium, creatinine, ASAT, ALAT, γ-GT, and pregnancy test.

^d Last safety samples are taken and analysed at visit 3, in the last treatment period only.

^e Whole blood sample taken in two 7/6 ml EDTA Vacutainers^®.

^f Patient fills in the electronic diary (PERSYVE Q) under supervision of study staff.

^g Q covering demographic items, medical history, smoking, and physical activity.

^h Dosing once daily in all treatment periods.

ⁱ When patients are dosing at home (between visit 2 and 3) symptoms will be recorded in PERSYVE Q using an electronic diary. Patients will report spontaneously but will also be prompted via SMS at three occasions: after 3, 5, and 7 weeks of dosing.

^j Details specified in a laboratory manual.

^k Adverse events recorded by clinical staff at visits 2 and 3 in each treatment period (observations, open questions, and reporting of symptoms spontaneously mentioned by patients). PERSYVE Q completed before the open AE question.

^l At visit 3 in each treatment period patients will fill out a treatment preference rating Q consisting of five questions covering willingness to pay, treatment preference, safety, and motivation.

^m 24-h BP/ECG at the end of each treatment period, between visits 3 and 4. Applied at visit 3 and removed the same time at visit 4.

ⁿ 24-h BP/ECG also at the end of placebo run-in to get a baseline assessment.

^o Overall patient preference rating and prescription of preferred study drug for continuous use.

Q = questionnaire.

Table 3. Inclusion and exclusion criteria.

Inclusion criteria

Male or female aged ≥40 years and ≤75 years

Previously diagnosed with hypertension with systolic blood pressure between 140 and 159 mmHg within 5 years prior to the start of the trial

Pharmacologically untreated or using blood pressure-lowering monotherapy at visit 1. No blood pressure-lowering medication taken during the placebo run-in period

Office systolic blood pressure between 140 and 179 mmHg and diastolic blood pressure at or below 109 mmHg at visit 2

Patients must give informed consent to participate in the study

Exclusion criteria

Medical history, clinical signs, or laboratory results indicating secondary hypertension, including primary aldosteronism or renal artery stenosis

Evidence of serious hematological, respiratory immunological, renal, hepatic, gastrointestinal, endocrinological, metabolic, neurologic, malignant, psychiatric, or other diseases as revealed by medical history, physical examination, and/or laboratory assessments

Active gout

Previous or present arterial occlusive diseases such as myocardial infarction (MI), stroke or acute arterial insufficiency (unstable angina pectoris or transient ischemic attacks [TIA]), or heart failure (NYHA class III or IV, or left ventricular systolic dysfunction irrespectively of function class)

Moderate or severe aortic or mitral insufficiency

Renal failure, including hemodialysis or kidney transplant(s)

Atrial fibrillation in need of rate control

Symptomatic hypotension, defined as weakness or syncope upon rising to an erect position associated with a decrease in systolic blood pressure

Diabetes requiring insulin or oral glucose-lowering drugs

Any history of serious abnormal drug reaction to active or inactive compounds in the study drugs, including angioedema

Any condition associated with poor compliance including alcoholism or drug dependence

Patients who will not comply with the study protocol as judged by the investigator

Women who are pregnant or lactating or not using appropriate contraception for at least 3 months prior to visit 1. Acceptable contraceptive methods are: combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, and vasectomized partner

Continuous use of concomitant medication that can interfere with study medication, i.e. digitalis glucosides, sotalol, cholestyramine, colestipol, NSAID, lithium, carbamazepine, CYP3A4-inhibitors, CYP3A4-inducers, dantrolene, diuretics, aliskiren, gold, sympathomimetics, tricyclic antidepressants, antipsychotics, anaesthetics, and potassium supplements

Clinical laboratory assessment outside normal range at visit 1 and judged clinically significant by the investigator

Previous randomization in present study

Table 4. Questionnaires.

At visit 1 the patients complete a questionnaire covering demographic items, medical history, smoking, and physical activity.

At visit 1 the patients complete a ‘Beliefs about medicine’ questionnaire.

At visit 2 after placebo run-in and at visit 3 after each treatment period, patients fill out a modified section 2.1 of the ‘PERSYVE’ questionnaire on paper in the clinic. Patients are also prompted via SMS to fill out the questionnaire at home at specific time points—at week 3, week 5, and week 7 of each treatment period, on paper or using an electronic diary (provided by Symptoms Europe AB, filled out via smartphone).

At visit 3 in each treatment period patients will fill out a ‘Treatment preference rating questionnaire’ consisting of five questions covering willingness to pay, treatment preference, safety, and motivation.

At visit 5 patients fill out an ‘Overall treatment preference rating’.

Table 5. Summary of power simulation.

Simulation model (mmHg): $SB{P}_i=\mathit{\text{Intercep}}{t}_i+In{d}_{\mathit{\text{TreatA}}}\times \mathit{\text{Treat}}{A}_i+In{d}_{\mathit{\text{TreatB}}}\times \mathit{\text{Treat}}{B}_i+In{d}_{\mathit{\text{TreatC}}}\times \mathit{\text{Treat}}{C}_i+In{d}_{\mathit{\text{TreatD}}}\times \mathit{\text{Treat}}{D}_i+{ϵ}_{i,\mathrm{ }\text{period}}$ Between-patient variation assumption: $\mathit{\text{Intercep}}{t}_i\sim \mathrm{ }N\left(\mathrm{0,14}\right)$ Within-patient variation assumption: ${ϵ}_{i,\text{period}}\sim N(\mathrm{0,12})$
Null hypothesis with N = 240 (for validation purpose, should be 5%) $\mathit{\text{Treat}}{A}_i=\mathrm{ }\mathit{\text{Treat}}{B}_i=\mathit{\text{Treat}}{C}_i=\mathrm{ }\mathit{\text{Treat}}{D}_i=0$
5.2%
Normally distributed individual treatment effects with SD = x mmHg $\mathit{\text{Treat}}{A}_i\sim \mathrm{ }N\left(0,a\right),\mathrm{ }\mathit{\text{Treat}}{B}_i\sim \mathrm{ }N\left(0,b\right),\mathrm{ }\mathit{\text{Treat}}{C}_i\sim \mathrm{ }N\left(0,c\right),\mathrm{ }\mathit{\text{Treat}}{D}_i\sim \mathrm{ }N\left(0,d\right)$
N = 240
	$x=5$	$x=7.5$	$x=10$
$a=b=c=0,d=x$	29%	82%	>99%
$a=b=0,c=d=x$	46%	97%	>99%
$a=0,b=c=d=x$	57%	>99%	>99%
$a=b=c=d=x$	64%	>99%	>99%
A fraction p of patients have x mmHg uniformly higher BP on treatment D (note that $SD\left(\mathit{\text{Treat}}{D}_i\right)=\sqrt{p\times \left(1-p\right)}\times x$, maximum SD=x/2 at 50% fraction) $\mathit{\text{Treat}}{D}_i\sim \mathrm{ }B(1,p)\times x$
N = 240
	$x=10$	$x=20$	$x=30$
$p=20\mathrm{\%}$	12%	90%	>99%
$p=50\mathrm{\%}$	27%	>99%	>99%