A study to check if Baxdrostat will reduce Blood pressure and is safe in patient with high Blood pressure

Phase 3

Active, not recruiting

• Conditions: Essential (primary) hypertension,

• Registration Number: CTRI/2024/02/062344
• Lead Sponsor: AstraZeneca AB

Brief Summary

This is a Phase III, multicentre, randomised, double-blinded, placebo-controlled, parallel group study to evaluate the safety, tolerability, and effect of 1 or 2 mg baxdrostat versus placebo, administered QD orally, on the reduction of SBP in approximately 720 participants aged ≥ 18 years with HTN, despite a stable regimen of 2 antihypertensive agents at baseline, one of which is a diuretic (uHTN); or ≥ 3 antihypertensive agents at baseline, one of which is a diuretic (rHTN).

Approximately 150 participants in Cohort 1 and 90 in Cohort 2 will be randomised to receive standard-of-care, as determined by the clinical judgement of the Investigator, in an open-label manner. Participants in Cohort 1 will receive this treatment for 40 weeks (from Week 12 to Week 52 and participants in Cohort 2 will receive this treatment for 12 weeks (from Week 12 up to Week 24. Upon completing this period of standard-of-care treatment, and prior to completing the overall study, participants will enter a 2-week safety follow-up period.During this treatment period, the Investigator may choose to continue background antihypertensive medication with or without the addition of additional agent(s). Mineralocorticoid receptor antagonists and potassium-sparing diuretics are permitted during this period and these agents may be used at the discretion of the Investigator. Any changes made in the antihypertensive therapy will be documented in the eCRF.

Placebo Single-Blind Run-in Period

Eligible participants who complete the Screening Visit procedures, willenter a 2-week single-blind run-in period and receive placebo in addition toany existing background antihypertensive mediation.

Double-Blind Placebo-Controlled Treatment Period

During this period, participants should remain on their backgroundantihypertensive medication regimen and dose. Doses of backgroundantihypertensive medication should not be changed during this period unlessparticipants experience SBP < 100 mmHg with symptoms of hypotension. Forparticipants who meet the criteria for receiving rescue antihypertensivemedication (SBP or DBP exceeds 170 or 105 mmHg, respectively), see Section6.9.2 of study protocol.

Open-Label Treatment Period

All participants randomised to 2 mg baxdrostat at Week 12 will receive 2mg baxdrostat in an open-label manner for 12 weeks (from Week 12 to Week 24),in addition to any existing background antihypertensive medication, which willbe subject to change at the Investigator’s discretion during this open-labelperiod (except for the addition of MRAs and potassium-sparing diuretics, whichare not permitted).

Randomised Withdrawal Double-Blind Period - Only Participants in Cohort 1

During this period, participants should remain on the same backgroundantihypertensive medication regimen and dose they receive at the start of thisperiod. Doses of background antihypertensive medication should not be changedunless participants experience SBP < 100 mmHg with symptoms of hypotension.Mineralocorticoid receptor antagonists and potassium-sparing diuretics areprohibited during this period. See Section 6.9.2 for details on rescueantihypertensive medication.

Second Open-Label Period in Cohort 1

Participants in Cohort 1 who complete the 8-week RWD double-blind periodwill enter this 20-week open-label period (Week 32 to Week 52) to receive 2 mgbaxdrostat QD, in addition to any existing background antihypertensivemedication. During this period, participant’s background therapy can be changedas per Investigator’s decision, but MRAs or potassium-sparing diuretics are notallowed.

Detailed Description

Not available

Study Timeline

• Study Start: 2024-03-16
• Last Update Posted: 2024-12-18

Recruitment & Eligibility

• Status: Closed to Recruitment of Participants
• Sex: All
• Target Recruitment: 720

Inclusion Criteria

• 1 Mean siSBP on AOBPM ≥ 140 mmHg and < 170 mmHg at Screening. 2 Fulfil at least 1 of the following 2 criteria: a.Participants in the uHTN subpopulation: have a stable regimen of 2 antihypertensive medications, from different therapeutic classes (at least one should be a diuretic), at maximum tolerated dose in the judgement of the Investigator, for at least 4 weeks prior to Screening (participants who do not meet this criterion may be rescreened at the Investigator’s discretion). Beta blockers used to treat other conditions (ie, migraine, HF, coronary artery disease) should not be counted as an antihypertensive medication for the purpose of qualifying for this study. b. Participants in the rHTN subpopulation: have a stable regimen of ≥ 3 antihypertensive medications, from different therapeutic classes (at least one should be a diuretic), at maximum tolerated dose in the judgement of the Investigator, for at least 4 weeks prior to Screening (participants who do not meet this criterion may be rescreened at the Investigator’s discretion). Beta blockers used to treat other conditions (ie, migraine, HF, coronary artery disease) should not be counted as an antihypertensive medication for the purpose of qualifying for this study. 3 Demonstrated good adherence to the prescribed antihypertensive medications by performing DOT during Visit 2 4 Estimated glomerular filtration rate ≥ 45 mL/min/1.73m2 at Screening. 5 Serum potassium (K+) level ≥ 3.5 and < 5.0 mmol/L at Screening determined as per central laboratory (participants who have serum K+ levels < 3.5 mmol/L may be rescreened at the Investigator’s discretion). 6 Morning cortisol levels (measured at 08:00 am ± 2 hours) ˃ 3 µg/dL. Sex and Contraceptive/Barrier Requirements 1 Only female participants: Contraceptive used by females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a Female participants: i Females not of child-bearing potential are defined as females who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Females will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause. The following age-specific requirements apply: ii Females < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone levels in the postmenopausal range. iii Females ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. iv Female participants of child-bearing potential must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. Females of child-bearing potential who are sexually active with a non- sterilised male partner must agree to use one highly effective method of birth control, as defined below, from 30 days before enrolment and throughout the study, and until at least 30 days after last dose of study intervention. v The following are not acceptable methods of contraception: periodic abstinence (calendar, symptom-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only and lactational amenorrhoea. Female condom and male condom should not be used together. vi All females of child-bearing potential must have a negative serum pregnancy test result at Screening and not be at stage of breastfeeding. vii Highly effective birth control methods include: Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments) ([periodic abstinence.
• eg, calendar, ovulation, sympto-thermal, post-ovulation methods.
• declaration of abstinence for the duration of exposure to study intervention and withdrawal are not acceptable methods of contraception]); a vasectomised partner; Implanon; bilateral tubal occlusion; intrauterine device/levonorgestrel intrauterine system; Depo-Proveraâ„¢ injections; oral contraceptive; and Evra Patch, Xulane or NuvaRing. Informed Consent 8 Capable of giving signed informed consent (including compliance with the requirements and restrictions listed in the Informed Consent Form [ICF] and in this protocol). See Appendix A 3 for details on the informed consent process. 9 Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative. Participation is voluntary and if a participant declines to participate there will be no penalty or loss of benefit. See Appendix D 2 for details. Randomisation Criteria These randomisation criteria only apply to the initial randomisation of the study. Participants are eligible to be randomised to a treatment group only if all the following criteria apply:Mean siSBP on attended office AOBPM of ≥ 135 mmHg at baseline (end of the run-in period) 12 Have an 80 to 120% adherence to placebo during the run-in period, based on pill counts on the morning of randomisation. 13 Have no change in background therapy regimen and dose consisting of either 2 antihypertensive medications (at least one should be a diuretic) for participants in the uHTN subpopulation, or ≥ 3 antihypertensive medications (at least one should be a diuretic) for participants in the rHTN subpopulation, for at least 4 weeks prior to randomisation (participants who do not meet this criterion may be rescreened at the Investigator’s discretion, Beta blockers used to treat other conditions (ie, migraine, HF, coronary artery disease) should not be counted as an antihypertensive medication for the purpose of qualifying for this study. 14 Demonstrated good adherence to the prescribed antihypertensive medications by performing DOT during Visit 2.

Exclusion Criteria

• Medical Conditions 1 As judged by the Investigator, any evidence which in the Investigator’s opinion makes it undesirable for the participant to participate in the study.
• 2 Mean siSBP 2 on attended office AOBPM ≥ 170 mmHg at randomisation (participants who do not meet this criterion may be rescreened at the Investigator’s discretion).
• 3 Mean seated DBP 3on attended office AOBPM ≥ 110 mmHg at randomisation (participants who do not meet this criterion may be rescreened at the Investigator’s discretion).
• 4 Current or prior treatment (within the 4 weeks before Screening) with angiotensin-receptor blockers and ACEIs (both taken simultaneously).
• 5 Serum sodium level < 135 mmol/L at Screening, determined as per central laboratory.
• 6 Has the following known secondary causes of hypertension: renal artery stenosis, uncontrolled or untreated hyperthyroidism, uncontrolled or untreated hypothyroidism, pheochromocytoma, Cushing’s syndrome, aortic coarctation.
• 7 New York Heart Association functional HF class IV at Screening.
• 8 Medical history of stroke, acute coronary syndrome, hypertensive encephalopathy, or hospitalisation for HF within 6 months prior to Screening.
• 9 Planned percutaneous coronary intervention/coronary artery bypass grafting or percutaneous coronary intervention/coronary artery bypass grafting done within 6 months prior to Screening.
• 10 Known current severe left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy and/or severe aortic valvular disease.
• 11 Left bundle branch block and any cardiac arrhythmia requiring treatment.
• 12 Persistent atrial fibrillation.
• 13 Known severe hepatic impairment, defined as Child-Pugh Class C, based on records that confirm documented medical history.
• 14 Uncontrolled diabetes with HbA1c > 10.0% (86 mmol/mol) at Screening.
• 15 Baseline QTcF > 470 msec.
• 16 Family history of Long QT syndrome.
• 17 Heart rate < 45 or > 110 beats/min in a resting position.
• 18 Participants suspected to have severe cardiac hypertrophy.
• 19 Participants who are pregnant or breastfeeding.
• 20 Participants with a diagnosis of adrenal insufficiency.
• 21 Any of the following related to COVID-19 infection (participants who meet this criterion may be rescreened at the Investigator’s discretion) a.
• Suspected (as judged by the PI) or confirmed COVID-19 infection within the last 4 weeks prior to Screening or t randomisation.
• Hospitalisation for COVID-19 within the last 12 weeks prior to Screening.
• Prior/Concomitant Therapy 22Prior medical treatment with any MRAs, antiarrhythmic medications, or potassium-sparing diuretic used within 4 weeks prior to Screening.
• 23Treatment with potassium binders within 2 months prior to Screening.
• 24Is expected to receive or is receiving any of the exclusionary drugs such as strong inducers of cytochrome P450 (CYP) 3A, chronic (taken more than 3 times a week for more than 3 months) use of NSAIDs, MRAs and/or chronic use of systemic steroids.
• If such QT prolonging drugs are still needed, the Investigator must ensure appropriate monitoring of ECGs and electrolytes are performed, as per clinical judgement.
• 26Current or prior treatment within 6 months prior to Screening with cytotoxic therapy.
• 27Treatment with K+ supplements are not prohibited but should be continuously assessed and monitored throughout the trial Prior/Concurrent Clinical Study Experience 27 Known hypersensitivity to baxdrostat or drugs of the same class or any of its excipients.
• Other 29 Participants working shifts (ie, shifts that comprise working hours at different times on different days).

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To assess the effect of 1 mg baxdrostat versus placebo on seated SBP at week 12	Change from baseline in seated SBP at Week 12.
To assess the effect of 2 mg baxdrostat versus placebo on seated SBP at week 12.	Change from baseline in seated SBP at Week 12.

Secondary Outcome Measures

Name	Time	Method
To assess the effect of treatment with baxdrostat 2 mg vs placebo on ambulatory 24-hour average SBP at Week 12.	The change from baseline in the mean ambulatory 24-hour SBP at Week 12 as measured by ABPM.
To collect and store optional genetic samples for future exploratory genetic research, as detailed in Appendix D of protocol.	To be reported in a separate report.
To assess the effect of 2 mg baxdrostat versus placebo on seated SBP at 8 weeks after randomised withdrawal.	Change from RWD baseline (Week 24) in seated SBP at Week 32.
To assess the effect of 1 mg baxdrostat versus placebo on seated DBP at Week 12.	Change from baseline in seated DBP at Week 12.
To assess the effect of 1 mg baxdrostat versus placebo on achieving seated SBP < 130 mmHg at Week 12.	Achieving seated SBP < 130 mmHg at Week 12.
To assess the effect of 2 mg baxdrostat versus placebo on seated SBP at Week 12 in the rHTN subpopulation.	Change from baseline in seated SBP at Week 12.
To assess the effect of 1 mg baxdrostat versus placebo on seated SBP at Week 12 in the rHTN subpopulation.	Change from baseline in seated SBP at Week 12
To assess the effect of treatment with baxdrostat 1 mg vs placebo on ambulatory 24-hour average SBP at Week 12.	The change from baseline in the mean ambulatory 24-hour SBP at Week 12 as measured by ABPM.
To assess the effect of treatment with 2 mg baxdrostat versus placebo on seated SBP at 4 weeks after randomised withdrawal.	Change from RWD baseline (Week 24) in seated SBP at Week 28.
To assess the effect of 2 mg baxdrostat versus placebo on seated DBP at Week 12.	Change from baseline in seated DBP at Week 12.
To evaluate the biomarkers related to the pharmacodynamic action of baxdrostat versus placebo on the RAAS pathway.	To be reported in a separate report.
To assess the effect of 2 mg baxdrostat versus placebo on achieving seated SBP < 130 mmHg at Week 12.	Achieving seated SBP < 130 mmHg at Week 12.
To assess the effect of treatment with baxdrostat 2 mg and baxdrostat 1 mg vs placebo on ambulatory 24-hour BP at Week 12.	•The change from baseline in ambulatory night-time average SBP at Week 12 as measured by ABPM.
To evaluate the pharmacokinetics of baxdrostat.	Plasma concentrations of baxdrostat.
To assess the proteomic signature (and changes in plasma proteomic profile) of aldosterone synthase inhibition by baxdrostat.	To be reported in a separate report.

Trial Locations

Locations (14)

Care Hospitals; 🇮🇳 Hyderabad, TELANGANA, India

Govind Ballabh Pant Institute of Postgraduate Medical Education and Research; 🇮🇳 Delhi, DELHI, India

GSVM Medical College, LPS Institute of Cardiology & Cardiac Surgery; 🇮🇳 Nagar, UTTAR PRADESH, India

IPGME&R and SSKM Hospital; 🇮🇳 Kolkata, WEST BENGAL, India

Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER); 🇮🇳 Pondicherry, PONDICHERRY, India

JSS Medical College, JSS Hospital; 🇮🇳 Mysore, KARNATAKA, India

Kasturba Medical College and Hospital; 🇮🇳 Kannada, KARNATAKA, India

Lalitha Super Specialities Hospital Pvt. Ltd.; 🇮🇳 Guntur, ANDHRA PRADESH, India

Manipal Hospital; 🇮🇳 Mysore, KARNATAKA, India

Max Super Speciality Hospital Saket (East Block) (A Unit of Devki Devi Foundation); 🇮🇳 Delhi, DELHI, India

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Care Hospitals

🇮🇳Hyderabad, TELANGANA, India

Dr Bhagavathula Kutumba Srinivasa Sastry

Principal investigator

9849599888

bkssastry@hotmail.com