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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05562934

Collaborator

(none)

170

Enrollment

Locations

Arms

16.1

Anticipated Duration (Months)

5.9

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Resistant Hypertension	Biological: Experimental drug Other: Placebo	Phase 2

Detailed Description

Subjects whose blood pressure is not under control despite treatment with triple antihypertensive medications, including an angiotensin converting enzyme blocker or angiotensin receptor blocker, a calcium channel blocker, and a thiazide or thiazide-like diuretic will be recruited into the study. Subjects will enter run-in period which lasts for approximately 2 weeks. Subjects whose blood pressure is still not under control at the end of the run-in period despite compliance with triple antihypertensive background treatment (i.e., with mean 24hr systolic blood pressure >135 mmHg) will be randomized to receive one of different dose levels of XXB750 or placebo SC. Overall, a total of approximately 170 participants will be randomized. 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). Ambulatory blood pressure monitoring will occur at baseline, Week 9, and Week 12 (primary endpoint timepoint). Office blood pressure will be measured at each office visit. Home blood pressure will be measured by the participants using provided devices on specified days throughout the study. Participants will be followed to monitor their safety for an additional 8 weeks during which time no active study medication will be given.

Each of the first randomized participants will be assigned to receive one of the lower doses of XXB750 or placebo. A DMC will review the safety and tolerability data of those participants when the first 40 participants have completed at least 5 weeks of the study and, contingent upon DMC's findings of their safety and tolerability experience, the highest XXB750 dose will be introduced in the remaining approximately 130 participants.

The primary clinical question of interest is: Is there a dose-response signal with different doses of XXB750 3 SC injections versus placebo in reducing the mean 24hr SBP at Week 12 from randomization in participants with rHTN, regardless of discontinuation from study treatment, regardless of change in the dose of allowed background antihypertensive medications and regardless of receiving prohibited concomitant medication?

Study Design

Study Type:

Interventional

Anticipated Enrollment :

170 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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.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.

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

Participants, investigator staff, persons performing the assessments, and the Novartis CTT (Clinical Trial Team) will remain blinded to the identity of the treatment from the time of randomization until database lock. The study site pharmacist/nurse or other designated qualified site personnel who prepares the study drug and the unblinded CRA will remain unblinded.

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 8, 2022

Anticipated Primary Completion Date :

Feb 12, 2024

Anticipated Study Completion Date :

Mar 12, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose 1 Lowest dose	Biological: Experimental drug SC injection
Experimental: Dose 2 Dose 2	Biological: Experimental drug SC injection
Experimental: Dose 3 Dose 3	Biological: Experimental drug SC injection
Experimental: Dose 4 Highest dose	Biological: Experimental drug SC injection
Placebo Comparator: Dose 5 Placebo	Other: Placebo SC injection

Outcome Measures

Primary Outcome Measures

Change from baseline in mean 24hr SBP at Week 12 [12 weeks]
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.

Secondary Outcome Measures

Change from baseline in mean 24hr SBP at Week 12 [12 weeks]
To evaluate the treatment effect of the highest XXB750 dose versus placebo in reducing the mean 24hr SBP from baseline to Week 12
Nocturnal SBP dipping expressed as (nighttime mean SBP/daytime mean SBP) at Week 12 [12 Weeks]
To characterize the dose-response relationship of XXB750 compared to placebo in the nocturnal SBP dipping at Week 12.
The proportions of participants achieving blood pressure control defined as mean 24hr SBP <130 mmHg and mean 24hr DBP <80 mmHg at Week 12 [12 weeks]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male and female participants who are ≥ 18 years old.
Signed informed consent prior to participation in the study.
Apparent rHTN at screening (Visit 1) defined as uncontrolled BP with an office msSBP ≥ 145 mmHg despite treatment with stable (i.e., unchanged for ≥4 weeks), maximally tolerated doses of three antihypertensive drugs of different classes, specifically an ACEI/ARB, a long-acting dihydropyridine CCB, and a thiazide or thiazide-like diuretic. Refer to Section 10.8 for minimum required doses of some commonly prescribed drugs in those classes.
Mean 24hr SBP ≥135 mmHg (measured by ABPM) at the end-of Run-in-Visit (Visit 30) on treatment with maximally tolerated doses of an ACEI/ARB, a long-acting dihydropyridine CCB, and a thiazide or thiazide-like diuretic.

Exclusion Criteria:

Office msSBP <140 mmHg at Visit 20 or Visit 30 OR office msSBP ≥180 mmHg or office msDBP ≥110 mmHg at the end-of-run-in visit (Visit 30) OR 24h mean SBP >170 mmHg or 24h mean DBP >105mmHg measured by ABPM at the end of the run-in (Visit 30).
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).
Estimated GFR <30 mL/min/1.73m2 using CKD-Epi equation at screening (Visit 1) or at end-of-run-in visit (Visit 30).
Serum potassium >5.0 mmol/L (or equivalent plasma potassium value) at screening or end-of-run-in visit (Visit 30).
Current therapy with a mineralocorticoid receptor antagonist (MRA) or received an MRA within the 4 weeks prior to screening.
Type I diabetes mellitus or uncontrolled Type II diabetes (defined as a plasma HbA1c ≥9%)
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.
Chronic non-paroxysmal atrial fibrillation.
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
History of a renal denervation procedure.
Mid-arm circumference ≥42 cm.
Hospitalization for hypertensive emergency / crisis within the 12 months prior to screening.
Received any antihypertensive medication other than the CCB, ACEI/ARB, and thiazide/thiazide-like diuretic components of the triple background antihypertensive therapy, including sacubitril/valsartan within the 4 weeks before screening (Visit 1). Participants receiving beta blockers and prostate-specific alpha blockers (e.g., tamsulosin) are allowed in the study only if those medications are being used for non-hypertension indications and benign prostatic hypertrophy, respectively.
Night shift workers.
History of presence of any other disease where the life expectancy is less than 3 years.
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.
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.
Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
History of drug abuse or alcohol dependency.
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.
Concurrent enrollment in any other investigational drug or device trial (participation in non-interventional registries is acceptable).
Requiring prolonged/regular use of NSAIDs or other prohibited medications during of the study (i.e., required use for longer than 1 week).
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Guntersville	Alabama	United States	35976
2	Novartis Investigative Site	Beverly Hills	California	United States	90211
3	Novartis Investigative Site	Sacramento	California	United States	95821-2134
4	Novartis Investigative Site	Tustin	California	United States	92780
5	Novartis Investigative Site	Lake Worth	Florida	United States	33467
6	Novartis Investigative Site	Owensboro	Kentucky	United States	42303
7	Novartis Investigative Site	Fort Washington	Maryland	United States	20744
8	Novartis Investigative Site	Oxon Hill	Maryland	United States	20745
9	Novartis Investigative Site	Greenville	South Carolina	United States	29607
10	Novartis Investigative Site	Manassas	Virginia	United States	20109
11	Novartis Investigative Site	Norfolk	Virginia	United States	23504
12	Novartis Investigative Site	Richmond	Virginia	United States	23219
13	Novartis Investigative Site	Adelaide	South Australia	Australia	5000
14	Novartis Investigative Site	Bordeaux Cedex		France	33075
15	Novartis Investigative Site	Paris cedex 18		France	75877
16	Novartis Investigative Site	Paris		France	75015
17	Novartis Investigative Site	Tours		France	37000
18	Novartis Investigative Site	Chikushino-city	Fukuka	Japan	818-8516
19	Novartis Investigative Site	Tsuchiura	Ibaraki	Japan	300-8585
20	Novartis Investigative Site	Kishiwada-city	Osaka	Japan	596-0042
21	Novartis Investigative Site	Chuo ku	Tokyo	Japan	104-0031
22	Novartis Investigative Site	Chuo-ku	Tokyo	Japan	103-0027
23	Novartis Investigative Site	Chuo-ku	Tokyo	Japan	103-0028
24	Novartis Investigative Site	Bardejov		Slovakia	085 01
25	Novartis Investigative Site	Kosice		Slovakia	040 01
26	Novartis Investigative Site	Presov		Slovakia	080 01
27	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
28	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46010
29	Novartis Investigative Site	Taipei		Taiwan	110

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT05562934

Other Study ID Numbers:

CXXB750B12201
2021-005738-41

First Posted:

Oct 3, 2022

Last Update Posted:

Jan 17, 2023

Last Verified:

Jan 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Novartis Pharmaceuticals

hypertension

resistant hypertension

rHTN

not controlled hypertension

Additional relevant MeSH terms:

Hypertension

Study Results

No Results Posted as of Jan 17, 2023