The Precision Hypertension Care Study
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      The PHYSIC study aims to investigate the potential for precision medicine in the treatment of
      high blood pressure.

      It is a double-blind, randomized, repeated cross-over trial with six treatment periods: four
      classes of blood pressure-lowering drugs where treatment with two classes are repeated for
      each patient. The classes of blood pressure-lowering drugs to be tested are a diuretic, a
      calcium channel blocker, an ACE-inhibitor and an angiotensin receptor blocker.
    

Detailed description: 
      It is unknown if there is a clinically relevant between-person difference in blood pressure
      response to a given drug, i.e. if there are responders and non-responders to the drug. If
      there is no major between-person variation in blood pressure response or side effects of a
      drug, then there is no potential for precision medicine. It is also unknown if between-
      person differences in blood pressure response are different for different drugs, and
      magnitudes of within- and between-person variations in side effects are particularly unknown.
      Resolving these issues are imperative for the possibilities of precision blood
      pressure-lowering treatment, and this study aims to initially answer those questions.

      If this study proves that there is potential for personalized blood pressure-lowering
      treatment, investigators will explore the most promising predictors of blood pressure and
      side effect response to the four major first-line classes of blood pressure-lowering drugs,
      using several modalities of -omics methods in combination with clinical data. Using these
      data, investigators will develop and evaluate a point-of-care biomarker panel which will rank
      the suitability of each of the blood pressure-lowering drug classes for the individual
      patient in terms of both anticipated blood pressure effect and side effects, thereby
      providing a suggestion of the priority of the drugs.

      The PHYSIC study is a double-blind, randomized, repeated cross-over trial with six treatment
      periods: four classes of blood pressure-lowering drugs where treatment with two classes are
      repeated for each patient. The classes of blood pressure-lowering drugs to be tested are a
      diuretic, a calcium channel blocker, an ACE-inhibitor and an angiotensin receptor blocker.
      The repeated treatment periods allow investigators to assess whether there is consistent
      preference of one treatment over another within a blinded patient under different treatment
      periods. This is a key but often overlooked element in the exploration of the potential for
      precision medicine.

      Evidence-based titration and target doses have been chosen for all four drug classes
      included. The suggested treatment duration of 7-9 weeks per treatment arm is based on recent
      guidelines. Patients will be assigned a treatment order based on block randomization ensuring
      that the same number of patients will repeat each pair of treatments. The study tests several
      pre-defined hypotheses, which will not be adjusted for multiple testing. The main outcome
      variable will be variation in daytime ambulatory systolic blood pressure assessed in a
      blinded fashion.

      The screening visit (visit 1) will occur at least two weeks before randomization (visit 2).
      At screening, consenting patients are assessed to ensure that they meet eligibility criteria
      initially. Patients who do not meet these criteria must not be enrolled in the study.
      Patients who do meet these criteria are allocated an enrolment number. The amount of
      assessment made at this visit includes consent procedures, weight, height, waist, and hip
      circumference, physical examination, concomitant medication, blood pressure, and blood
      sampling for safety assessment and DNA genetics. The patient will fill out two questionnaires
      covering medical history and beliefs about medicine. In order to be introduced to
      self-reporting symptoms and quality of life collected in electronic diary and get a baseline
      measurement patients will be asked to log in to and fill the diary under supervision of study
      staff.

      After the screening visit, the patient stops taking any blood pressure-lowering drugs and
      starts on an unblinded placebo treatment run-in period of two weeks to establish an untreated
      baseline to be used for characterization of the study sample. During this placebo run-in
      patients will have access to the electronic diary for reporting symptoms and quality of life.
      Patients will also be prompted via sms to fill out this diary at home once during this
      period.

      At visit 2, eligibility criteria will be checked once again. Concomitant medication will be
      checked and blood pressure measured. Other blood pressure-lowering drugs are not allowed as
      concomitant medication. Baseline assessments made at this visit includes venous blood
      sampling (DNA methylation, RNA, proteins and metabolites), capillary blood sampling, safety
      sampling, pulse wave analysis, initiation of the 24h blood pressure and ECG measurement. The
      study staff will also collect AE ́s via open question and observations. Furthermore patients
      will also fill out a validated questionnaire to measure perceived symptoms associated with
      antihypertensive drugs (PERSYVE).

      If all criteria are met, the patient will be randomized to the consecutive randomization
      number and given the first investigational product (IP). The IP will be taken once daily.
      Each treatment period will be 7-9 weeks (titration dose 2 weeks + target dose 5-7 weeks) and
      dosing will take place at home.

      The day after visit 2 patients will return the 24 h blood pressure and ECG equipment to the
      clinic.

      Between visit 2 and 3 patients are dosing at home. Throughout the study, patients will have
      access to an electronic diary for reporting symptoms and quality of life, using a validated
      questionnaire, PERSYVE (only section 2.1 in questionnaire will be used in this study).
      Patients will also be prompted via sms to fill out these this questionnaire at home at
      specific time points - at week 3, week 5 and week 7 of each treatment period.

      At visit 3 of each treatment period the patient will come fasting to the clinic for venous
      blood sampling (DNA methylation, RNA, proteins and metabolites), capillary blood sampling,
      pulse wave analysis, concomitant medication check, blood pressure measurement, and initiation
      of the 24h blood pressure and ECG measurement. The study staff will also collect adverse
      events (AEs) via open question and observations. All AEs will be assessed by the Principal
      Investigator. Furthermore, patients will also fill out two paper questionnaires; PERSYVE
      section 2.1 (identical to questionnaire in electronic diary) and a treatment preference
      rating questionnaire. The patient will return all unused IP to site, except for 1 capsule
      which will be taken the following day. The study personnel will give the patient the next
      treatment and the patient will undergo a batch, which starts with a 7- day placebo washout
      period before the next active drug treatment period starts. Lastly, blood samples are
      obtained and analyzed for safety parameters at visit 3 in the last treatment period only.

      At visit 4 (the Week 8 visit) the 24h blood pressure and ECG measurement will end.

      One week after visit 4 in the last treatment period, the patient comes to the clinic for a
      last visit. During this visit the patient will be asked to do an overall treatment preference
      rating including all treatment periods. An independent and unblinded study physician will be
      delegated to break the blind for each completed patient and prescribe the preferred IP for
      continuous use.
    

Intervention name(s): Zestril®; Atacand®; Norvasc®; Hydrochlorthiazide®; Treatment X; Treatment Y; Placebo
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Treatment step up: 1-2 weeks (10 mg tablet) Target dose: 5-7 weeks (20 mg tablet); Treatment step up: 1-2 weeks (8 mg tablet) Target dose: 5-7 weeks (16 mg tablet); Treatment step up: 1-2 weeks (5 mg tablet) Target dose: 5-7 weeks (10 mg tablet); Treatment step up: 1-2 weeks (12,5 mg tablet) Target dose: 5-7 weeks (25 mg tablet); Each patient receives all four treatments, and in addition repeats two of the treatments, labeled X and Y. The repeated arms will be given with the same duration and dosing as the other arms.; Each patient receives all four treatments, and in addition repeats two of the treatments, labeled X and Y. The repeated arms will be given with the same duration and dosing as the other arms.; This is an unblinded placebo run-in which we use to generate baseline values. Each patient will initiate their participation with these 2 weeks of placebo treatment, taking 1 capsule daily.
Other intervention name(s): Lisinopril; Candesartan; Amlodipine; Hydrochlorthiazide
Intervention MeSH terms: Amlodipine; Candesartan; Candesartan cilexetil; Lisinopril
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment