An Efficacy, Safety, Tolerability and Dose Finding Study of XXB750 in Resistant Hypertension Patients.

Resistant Hypertension Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05562934
• Other study ID #: CXXB750B12201
• Secondary ID: 2021-005738-41
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 8, 2022
• Est. completion date: August 27, 2024

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 191
• Est. completion date: August 27, 2024
• Est. primary completion date: July 2, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hypertension
• Resistant Hypertension

Intervention

Biological:
• Experimental drug
SC injection

Other:
• Placebo
SC injection

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Perth	Western Australia
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Wien
Bulgaria	Novartis Investigative Site	Pleven
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
China	Novartis Investigative Site	Baotou	Inner Mongolia
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Qingdao
China	Novartis Investigative Site	Shanghai
Czechia	Novartis Investigative Site	Brandys nad Labem	Czech Republic
Czechia	Novartis Investigative Site	Praha 2	CZE
France	Novartis Investigative Site	Bobigny cedex	Seine Saint Denis
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Tours
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Elsterwerda
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Ulm
Italy	Novartis Investigative Site	Bologna
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Pisa	PI
Japan	Novartis Investigative Site	Chikushino-city	Fukuka
Japan	Novartis Investigative Site	Chuo ku	Tokyo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Kanazawa	Ishikawa
Japan	Novartis Investigative Site	Kishiwada-city	Osaka
Japan	Novartis Investigative Site	Yokohama city	Kanagawa
Japan	Novartis Investigative Site	Yokosuka	Kanagawa
Netherlands	Novartis Investigative Site	Amsterdam
Poland	Novartis Investigative Site	Gdynia
Poland	Novartis Investigative Site	Katowice
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Wroclaw
Slovakia	Novartis Investigative Site	Bardejov
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Lucenec
Slovakia	Novartis Investigative Site	Nitra
Slovakia	Novartis Investigative Site	Svidnik
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Pamplona	Navarra
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Terrassa	Catalunya
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
United Kingdom	Novartis Investigative Site	London	GBR
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Salford
United States	American Clinical Trials Nephrology	Acworth	Georgia
United States	Pinnacle Research Group Llc .	Anniston	Alabama
United States	Parkway Medical Center Research Department	Birmingham	Alabama
United States	Anderson Medical Research	Fort Washington	Maryland
United States	The Research Center of the Upstate	Greenville	South Carolina
United States	Jacksonville Ctr for Clin Rea Main Centre	Jacksonville	Florida
United States	Canvas Clinical Research	Lake Worth	Florida
United States	Capitol Cardiology Associates	Lanham	Maryland
United States	NexGen Research	Lima	Ohio
United States	Manassas Clinical Research Center .	Manassas	Virginia
United States	Inpatient Research Clinical LLC	Miami Lakes	Florida
United States	MD Medical Research	Oxon Hill	Maryland
United States	Dominion Medical Associates .	Richmond	Virginia
United States	Clinical Trials Research Sacramento	Sacramento	California
United States	Tennessee Center For Clinical Trials .	Tullahoma	Tennessee
United States	Orange County Research Center Research	Tustin	California
United States	Cardiology Partners Clinical Research Institute	Wellington	Florida
United States	Alliance for Multispecialty Resrch Research	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Bulgaria,  China,  Czechia,  France,  Germany,  Italy,  Japan,  Netherlands,  Poland,  Slovakia,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in mean 24hr SBP at Week 12	To evaluate the efficacy and dose-response relationship of different doses of XXB750 SC compared to placebo in reducing the mean 24hr ambulatory systolic blood pressure (mean 24hr SBP) from baseline at Week 12.	12 weeks
Secondary	Change from baseline in mean 24hr SBP at Week 12	To evaluate the treatment effect of the highest XXB750 dose versus placebo in reducing the mean 24hr SBP from baseline to Week 12	12 weeks
Secondary	Average of changes from baseline in mean 24hr SBP at Week 9 and at week 12	To evaluate the treatment effect of the highest XXB750 dose versus placebo in the dosing interval average of ambulatory SBP as assessed by average of mean 24hr SBP measured at week 9 and week 12	Baseline, week 9 and week 12
Secondary	The proportions of participants achieving blood pressure control defined as mean 24hr SBP <130 mmHg and mean 24hr DBP <80 mmHg at Week 12	To evaluate the proportions of participants achieving ambulatory BP control (i.e., mean 24hr SBP < 130 mmHg and mean 24hr DBP < 80 mmHg) with respect to the dose-response relationship of the four XXB750 dose level groups compared to placebo at week 12.	12 weeks