CTRI/2025/09/094937尚未招募3 期
A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy and Safety of Baxdrostat in Adult Participants with Primary Aldosteronism
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 180
- 试验地点
- 6
- 主要终点
- To assess the effect of baxdrostat versus placebo on seated SBP at Week 8
研究概览
简要总结
Aldosterone is a hormone that has been implicated in CV and renal diseases by causing HTN and promoting cardiac, renal, and vascular damages. Aldosterone is the principal mineralocorticoid in humans, and it is synthesised in the adrenal cortex by the enzyme aldosterone synthase. Aldosterone is a key component of the RAAS and acts as a critical regulator of fluid and electrolyte homeostasis through its agonism of the MR. Aldosterone s effect on end organs has been shown to occur via its direct interaction with the MR (genomic effect), in addition to mechanisms independent of that direct interaction (non-genomic- or non-receptor-mediated effects) (Duprez 2007, Sato and Saruta 2004). Many patients with HTN have inappropriately high aldosterone concentrations that promote cardiac, renal, and vascular injury. BP can be significantly reduced by partially inhibiting the activity of the RAAS.
Inhibiting aldosterone synthesis represents a promising target for the reduction of BP and mitigation of BP-dependent end-organ damage (Brown 2024, Marney and Brown 2007). However, one of the challenges that has prevented the development of aldosterone synthase inhibitors in previous drug development programs has been the difficulty in selectively inhibiting aldosterone synthase without also reducing the synthesis of cortisol. The synthesis pathway of cortisol is catalysed by 11 beta -hydroxylase (CYP11B1), which shares high sequence homology (93percentage) with aldosterone synthase (CYP11B2).
Undesired inhibition of 11 beta -hydroxylase leads to suppression of cortisol levels and compromised stress and immunologic responses, and possibly increased mortality rates (Oelkers 1996, Wagner and White 1984, Wagner et al 1984). Baxdrostat is a highly potent and selective competitive inhibitor of human aldosterone synthase (encoded by the CYP11B2 gene) with a selectivity ratio of 100:1 over CYP11B1 (Bogman et al 2017, Freeman et al 2023a). In nonclinical and clinical studies, baxdrostat significantly lowered aldosterone levels without affecting cortisol levels over a wide dose range. Therefore, baxdrostat may be a novel treatment for the deleterious effects of inappropriately elevated aldosterone levels, thus reducing BP and the potential for aldosterone-mediated end-organ damage
AstraZeneca is developing baxdrostat in 2 indications: treatments of adults with HTN (uHTN and rHTN) and PA. Furthermore, baxdrostat is being developed as a fixed-dose combination with dapagliflozin in 2 indications: treatment of CKD in adults with CKD and HTN and prevention of HF in adults with T2DM, a history of HTN, and established CV disease at increased risk for HF
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- Participant and Investigator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Age 1 Male or female participants must be greater than or equal to 18 years of age at the time of signing the informed consent.
- •Type of Participant and Disease Characteristics 2 Participants with a documented diagnosis of PA that fulfils the criteria defined in the 2016 or 2025 Endocrine Society Guidelines.
- •Note: Patients with unilateral adrenal adenoma potentially eligible for curative adrenalectomy may elect to not undergo or delay surgery.
- •In this case they would also be eligible to enrol in the study.
- •3 Are willing and able to cease dosing of MRA or potassium-sparing diuretics per study requirement for participants taking an MRA or potassium-sparing diuretic at Screening.
- •4 eGFR greater than or equal to 45 mL/min/1.73m2 at Screening as per the central laboratory1 5 Serum potassium level greater than or equal to 3.0 and less than 5.0 mmol/L at Screening determined as per the central laboratory.
- •If potassium less than 3.0 or greater than or equal to 5.0 mmol/L at Screening the test will be repeated.
- •Participants with serum potassium less than 3.5 mmol/L may continue in the study if the Investigator elects to correct the serum potassium level with supplementation.
- •Sex and Contraceptive/Barrier Requirements 6 Female participants assigned at birth inclusive of all gender identities: Contraceptive use 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 less than 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 greater than or equal to 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 throughout the study and until at least 30 days after last dose of study intervention.
- •(v) The following are not acceptable methods of contraception: male or female condom periodic abstinence (eg calendar ovulation symptom-thermal post- ovulation methods declaration of abstinence for the duration of exposure to study intervention) withdrawal (coitus interruptus) spermicides only and lactational amenorrhoea.
- •(vi) All females of child-bearing potential must have a negative pregnancy test result (serum) 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) vasectomised partner; Implanon®; bilateral tubal occlusion; intrauterine device/levonorgestrel intrauterine system; Depo-Provera™ injections; oral contraceptive associated with inhibition of ovulation; and Evra Patch™ Xulane™ or NuvaRing®.
- •Informed Consent 7 Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- •8 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.
- •1.1.1 Additional Randomisation Criteria at Visit 2 To be eligible for randomisation in the study participants must have met all screening criteria at Visit 1 as well as the following additional randomisation criteria at Visit 2: 9 Mean seated SBP on AOBPM of greater than or equal to 135 mmHg. Note if a participant completes the MRA wash-out period and has SBP less than 135 mmHg the visit will be designated Visit 1.5 and the participant will undergo a further 2 weeks of MRA wash-out (In this case Visit 2 will take place 2 weeks after the start of the extended wash-out period.
- •11 Serum potassium greater than 3.0 mmol/L.
排除标准
- •Participants are excluded from the study if any of the following criteria apply: 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 If not taking an MRA or potassium-sparing diuretic at Screening: Mean seated SBP greater than 180 mmHg or mean seated DBP greater than or equal to 110 mmHg (on AOBPM). If taking an MRA or potassium-sparing diuretic at Screening: Mean seated SBP greater than 160 mmHg or mean seated DBP greater than or equal to 100 mmHg. 3 Previous surgical intervention for an adrenal adenoma or have a planned adrenalectomy, renal nerve denervation, or adrenal ablative procedure during the course of the study. Note: Participants who have had a procedure greater than 6 months prior to Screening but still have elevated serum/plasma aldosterone concentration ( greater than 15 ng/dL) and meet BP and other eligibly criteria may be considered. 4 Has the following known secondary causes of HTN: renal artery stenosis, uncontrolled or untreated hyperthyroidism, uncontrolled or untreated hypothyroidism, pheochromocytoma, Cushing s syndrome, aortic coarctation. 5 Serum sodium level less than 135 mmol/L at Screening, determined as per central laboratory. 6 New York Heart Association functional HF class IV at Screening. 7 Medical history of stroke, acute coronary syndrome, hypertensive encephalopathy, or hospitalisation for HF within 6 months prior to Screening. 8 Planned percutaneous coronary intervention/coronary artery bypass grafting or percutaneous coronary intervention/coronary artery bypass grafting done within 6 months prior to Screening. 9 Known current severe left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy and/or severe aortic valvular disease. 10 Persistent atrial fibrillation. 11 Known severe hepatic impairment, defined as Child-Pugh Class C, based on records that confirm documented medical history. 12 Uncontrolled diabetes with HbA1c greater than 10.0% (86 mmol/mol) at Screening. 13 Heart rate less than 45 or greater than 110 beats/min in a resting position, as per vital signs assessment. 14 Participants suspected to have severe cardiac hypertrophy. 15 Participants who are pregnant or breastfeeding. 16 Participants with a diagnosis of adrenal insufficiency. Prior/Concomitant Therapy 17 Treatment with any MRA or potassium-sparing diuretic within 2 weeks prior to Randomisation. 18 Current or prior treatment (within the 4 weeks before Screening) with angiotensin- receptor blockers and ACEIs (both taken simultaneously). 19 Treatment with potassium binders within 2 months prior to Screening. 20 Expected to receive or is receiving any of the exclusionary drugs such as strong inducers of CYP3A, chronic (taken more than 3 times a week for more than 3 months) use of NSAIDs (use of low-dose aspirin is permitted, as per medical judgement), MRAs and/or chronic use of systemic steroids. 21 Current or prior treatment within 6 months prior to Screening with cytotoxic therapy. Prior/Concurrent Clinical Study Experience 22 Participants with a known hypersensitivity to baxdrostat or drugs of the same class or any of the excipients of the product. 23 Participation in another clinical study with baxdrostat or another investigational product administered in the 3 months before randomisation in this study. Other Exclusions 24 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 25 Judgement by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. 26 Previous randomisation in the present study. 27 For females only.
- •currently pregnant (confirmed with positive pregnancy test) or breast-feeding. 28 Participants working shifts (ie, shifts that comprise working hours at different times on different days). 1.2 Lifestyle Considerations No lifestyle restrictions such as diet, smoking habits, alcohol restrictions, etc. are required to participate in this study. 1.2.1 Meals and Dietary Recommendations Generally, no dietary restrictions are required but the following recommendations apply. Participants can take the study intervention with or without food. If participants have abnormal potassium and/or sodium, dietary counselling may be provided. Hyperkalaemia should be managed as per local standard-of-care. Participants should be instructed to maintain their usual fluid intake as best as possible, unless additional oral hydration is needed. If the participant is suspected to be dehydrated, closer supervision, including potassium monitoring is warranted. Investigators should also consider encouraging participants to limit potassium rich foods intake and to follow other main guidelines, such as:.
- •Avoid drinking liquid from canned fruits or vegetables.
- •Eat a variety of foods but in moderation.
- •Moderate serving size for each meal.
- •Always read the labels of any prepared foods.
- •Leach one s favourite high potassium vegetable to remove some of the potassium. Foods that contain high potassium include:.
- •Fruits: bananas, cantaloupe, honeydew, oranges, nectarines, kiwi, mango, papaya, prunes, watermelon, pomegranate, dates, dried fig, dried fruits.
- •Vegetables: avocados, broccoli, brussels sprouts, sweet potatoes, parsnips, pumpkin, tomato and tomato-based products, white potatoes, vegetable juices, winter squash.
- •Other: tofu, milk, yogurt, ice-cream, chocolate, granola, nuts, peanut butter, salt substitutes. 1.2.2 Caffeine, Alcohol, and Tobacco Prior to each visit with PD sampling, participants will abstain from alcohol for 24 hours before the start of dosing until after collection of the PD sample. Participants who use tobacco products will be instructed that use of nicotine-containing products (including nicotine patches) will not be permitted while they are in the clinical unit.
结局指标
主要结局
To assess the effect of baxdrostat versus placebo on seated SBP at Week 8
时间窗: To assess the effect of baxdrostat versus placebo on seated SBP at Week 8 | Achieving unsuppressed PRA at Week 8 in participants with suppressed PRA
To assess the effect of baxdrostat versus placebo on achieving unsuppressed PRA at Week 8 in participants with suppressed PRA
时间窗: To assess the effect of baxdrostat versus placebo on seated SBP at Week 8 | Achieving unsuppressed PRA at Week 8 in participants with suppressed PRA
次要结局
- To assess the effect of baxdrostat versus placebo on seated SBP 8 weeks after RWD(Change from RWD baseline (Week 44) in seated SBP at Week 52)
- To assess the effect of baxdrostat on the percent change in PRA 8 weeks after RWD(Percent change from RWD baseline (Week 44) in PRA at Week 52)
- To assess the effect of baxdrostat versus placebo on achieving serum potassium greater than or equal to 3.7 mmol/L without potassium supplementation at Week 8 in participants with serum potassium less than 3.7 mmol/L or potassium supplementation at baseline(Achieving serum potassium greater than or equal to 3.7 mmol/L without potassium supplementation at Week 8 in participants with serum potassium less than 3.7 mmol/L or potassium supplementation at baseline)
- To assess the effect of baxdrostat versus placebo on the percent change from baseline in PRA at Week 8(Percent change from baseline in PRA at Week 8)
- To assess the effect of baxdrostat versus placebo on achieving 24-hour urine aldosterone less than 10 µg at(Week 8 in participants with 24-hour urine aldosterone greater than or equal to 10 µg at baseline)
- To assess the effect of baxdrostat versus placebo on 24-hour urine albumin at Week 8(Change from baseline in 24-hour urine albumin at Week 8)
研究者
Dr Rajesh Khadgawat
All India Institute of Medical Sciences
研究点 (6)
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