Clinical trial NCT05562934: An Efficacy, Safety, Tolerability and Dose Finding Study of XXB750 in Resistant Hypertension Patients.
Official title: A Multi-center, Randomized, Double-blind, Parallel-group, 20-week Dose-finding Study to Evaluate Efficacy, Safety, and Tolerability of XXB750 in Patients With Resistant Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Resistant Hypertension
Keywords: hypertension
resistant hypertension
rHTN
not controlled hypertension
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2022-10-03
Enrollment: 191
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The planned duration of treatment is 12 weeks per participant. Participants may be discontinued from treatment earlier due to unacceptable adverse events, disease progression and/or if treatment is discontinued at the discretion of the investigator or the participant. Following the conclusion of the 12-week Randomized Treatment Period, participants will enter an 8-week Safety Follow-up Period in which participants may be treated at the discretion of the investigator taking into account that their blood pressure may still be affected by the study treatment for some time after its discontinuation, especially those who were randomized to XXB750.
Primary purpose: TREATMENT

Brief summary: The purpose of this 20-week randomized double-blind study in patients with resistant hypertension (rHTN) is to evaluate the efficacy, safety, and tolerability, of different doses of XXB750 administered as subcutaneous (SC) injections, compared to placebo. Since all study participants will be patients with rHTN, all study treatments will be given on top of maximally tolerated background antihypertensive therapy recommended by international guidelines for treatment of HTN (i.e., a thiazide or a thiazide-like diuretic, an angiotensin converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), and a long-acting dihydropyridine calcium channel blocker (CCB).

Detailed description: Subjects will enter run-in period which lasts for approximately 2 weeks. The study duration is for 20 weeks during which each participant will receive a total of 3 doses of study medication (in addition to 1 dose of study medication during run-in). Participants will be followed to monitor their safety for an additional 8 weeks during which time no active study medication will be given.

Eligibility criteria: Inclusion Criteria:

1. Male and female participants who are ≥ 18 years old.
2. Signed informed consent prior to participation in the study.
3. Apparent rHTN at screening (Visit 1) defined as uncontrolled BP with an office msSBP ≥ 140 mmHg despite treatment with stable (i.e., unchanged for ≥4 weeks), optimal or maximally tolerated doses of three or four antihypertensive drugs of different classes, including an ACEI/ARB, a long-acting dihydropyridine CCB, and a thiazide or thiazide-like diuretic. Participant with documented intolerance to any doses of CCBs may be eligible if receiving another class of antihypertensive medication at an optimal or maximally tolerated dose (referred to as triple background antihypertensive therapy. An optimal dose is defined as the highest dose taking in to account participant's documented comorbidities and tolerability per investigator's clinical judgment.
4. Mean 24hr SBP ≥135 mmHg (measured by ABPM) at the end-of Run-in-Visit (Visit 30) on treatment with optimal or maximally tolerated doses of an ACEI/ARB, a long-acting dihydropyridine CCB (or a suitable alternative in case of intolerance per inclusion criterion above), and a thiazide or thiazide-like diuretic.

Exclusion Criteria:

1. Subjects with the following blood pressures at the specified time points are not eligible to participate in the study:

   1. Office msSBP \<140 mmHg at Visit 20 OR
   2. Office msSBP ≥180 mmHg or office msDBP ≥110 mmHg at the end-of-run-in visit (Visit 30) OR
   3. 24h mean SBP \>170 mmHg or 24h mean DBP \>105mmHg measured by ABPM at the end of the run-in (Visit 30).
2. Known history of secondary hypertension (moderate-to-severe obstructive sleep apnea without receiving CPAP therapy (either face mask or nasal device), renovascular hypertension, primary aldosteronism, pheochromocytoma, Cushing syndrome, aortic coarctation or other cause of secondary hypertension).
3. Estimated GFR \<30 mL/min/1.73m2 using CKD-Epi equation at screening (Visit 1) or at end-of-run-in visit (Visit 30).
4. Serum potassium \>5.0 mmol/L (or equivalent plasma potassium value) at screening or end-of-run-in visit (Visit 30).
5. Current therapy with a mineralocorticoid receptor antagonist (MRA) or sacubitril/valsartan or received an MRA or sacubitril/valsartan within the 4 weeks prior to screening.
6. Type I diabetes mellitus or uncontrolled Type II diabetes (defined as a plasma HbA1c ≥9%)
7. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), high-grade AV block (e.g., Mobitz type II and third-degree AV block in absence of a pacemaker) within 6 months of screening according to investigator's judgement.
8. Chronic non-paroxysmal atrial fibrillation.
9. Acute myocardial infarction (AMI) or unstable angina, or any history of ischemic or hemorrhagic stroke within 12 months of screening; or any percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) within 12 months of screening
10. History of a renal denervation procedure.
11. Mid-arm circumference ≥44 cm. The cuff should snugly fit on the arm with out the margins of cuff overhanging arm musculature.
12. Patients with history of hospitalisation for hypertensive emergencies characterised by severe hypertension (usually grade 3) associated with funduscopic changes (flame haemorrhages and/or papilloedema), microangiopathy, disseminated intravascular coagulation, encephalopathy, acute aortic dissection, acute myocardial ischaemia, or acute heart failure any time prior to screening or hospitalisation for non-emergent/non-urgent uncontrolled hypertension without target organ damage within 3 months prior to screening
13. Receiving more than 4 antihypertensive medications.
14. Night shift workers.
15. History of presence of any other disease where the life expectancy is less than 3 years.
16. History of malignancy of any organ system (other than localized basal or squamous cell carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 3 years, regardless of whether there is evidence of local recurrence or metastases.
17. Evidence of hepatic disease as determined by any one of the following: SGOT (AST) or SGPT (ALT) values exceeding 3x the upper limit of normal (ULN), or bilirubin \>1.5 mg/dl at Visit 1.
18. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
19. History of drug abuse or alcohol dependency.
20. Lacking the ability to comprehend or follow instructions, or for any reason in the opinion of the investigator, a participant that would be unlikely or unable to comply with study protocol.
21. Concurrent enrollment in any other investigational drug or device trial (participation in non-interventional registries is acceptable).
22. Requiring prolonged/regular use of NSAIDs except for prophylactic use of low dose aspirin up to 325 mg QD or other prohibited medications during of the study (i.e., required use for longer than 1 week).
23. Pregnant, nursing or planning to become pregnant (documented negative pregnancy test required within a maximum of 7 days prior to enrollment of all women of childbearing potential). Documentation of highly effective contraception is also required for women of childbearing potential (see below).

    Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 3 months after stopping medication. Highly effective contraception methods include:
    * Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.
    * Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant.
    * Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormone vaginal ring or transdermal hormone contraception.

    In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

    Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms). Women are considered not of childbearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential.

    If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.
24. History of hypersensitivity to any of the study drugs, excipients or drugs of similar class.

Primary outcomes:
measure: Change from baseline in mean 24hr SBP at Week 12
timeFrame: 12 weeks
Secondary outcomes:
measure: Change from baseline in mean 24hr SBP at Week 12
timeFrame: 12 weeks
measure: Average of changes from baseline in mean 24hr SBP at Week 9 and at week 12
timeFrame: Baseline, week 9 and week 12
measure: The proportions of participants achieving blood pressure control defined as mean 24hr SBP <130 mmHg and mean 24hr DBP <80 mmHg at Week 12
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group Llc
state: Alabama
city: Birmingham
country: United States
facility: Parkway Medical Center
state: Alabama
city: Sacramento
country: United States
facility: Clinical Trials Research Sacramento
state: California
city: Tustin
country: United States
facility: Orange County Research Center
state: California
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Lake Worth
country: United States
facility: Canvas Clinical Research
state: Florida
city: Miami Lakes
country: United States
facility: Inpatient Research Clinical LLC
state: Florida
city: Wellington
country: United States
facility: Cardiology Partners Clinical Research Institute
state: Florida
city: Acworth
country: United States
facility: American Clinical Trials
state: Georgia
city: Wichita
country: United States
facility: Alliance for Multispecialty Resrch
state: Kansas
city: Fort Washington
country: United States
facility: Anderson Medical Research
state: Maryland
city: Lanham
country: United States
facility: Capitol Cardiology Associates
state: Maryland
city: Oxon Hill
country: United States
facility: MD Medical Research
state: Maryland
city: Lima
country: United States
facility: NexGen Research
state: Ohio
city: Greenville
country: United States
facility: The Research Center of the Upstate
state: South Carolina
city: Tullahoma
country: United States
facility: Tennessee Center For Clinical Trials
state: Tennessee
city: Manassas
country: United States
facility: Manassas Clinical Research Center
state: Virginia
city: Richmond
country: United States
facility: Dominion Medical Associates
state: Virginia
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Perth
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Graz
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Pleven
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Baotou
country: China
facility: Novartis Investigative Site
state: Inner Mongolia
city: Beijing
country: China
facility: Novartis Investigative Site
city: Qingdao
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Brandys nad Labem
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Bobigny
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Tours
country: France
facility: Novartis Investigative Site
city: Elsterwerda
country: Germany
facility: Novartis Investigative Site
state: Brandenburg
city: Frankfurt Am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Chikushino-city
country: Japan
facility: Novartis Investigative Site
state: Fukuka
city: Kanazawa
country: Japan
facility: Novartis Investigative Site
state: Ishikawa
city: Yokohama city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Yokosuka
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Kishiwada-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Chuo Ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Gdynia
country: Poland
facility: Novartis Investigative Site
city: Katowice
country: Poland
facility: Novartis Investigative Site
city: Krakow
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Bardejov
country: Slovakia
facility: Novartis Investigative Site
city: Kosice
country: Slovakia
facility: Novartis Investigative Site
city: Nitra
country: Slovakia
facility: Novartis Investigative Site
city: Svidnik
country: Slovakia
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Terrassa
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
state: GBR
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Salford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: