301 Proto Flashcards
Primary objective?
effect of IP when added to AHT on SBP in pts with HTN
Secondary objectives? (5)
- SBP control
- effect of 50->100mg up titration
- effect on 2 AHT meds
- effect on 3 or more
- effect on SBP with obesity
Exploratory objectives? (4)
- effect on DBP
- effect on MAP
- effect on UACR
- effect of demographics, med hx, concomitant meds, clinical and lab assessments on SBP lowering effect
Other objectives? (2)
- safety
- PK
Primary endpoint
effect of 50mg by week 6 across both IP treatment arms
Secondary endpoints (6)
All vs placebo
1. % AOBP SBP <130 by week 6 with 50mg
2. change in AOBP by week 12 in arm 3 (50->100mg)
3. Change in AOBP SBP by week 6 w/2x AHT meds
4. Change in AOBP SBP by week 6 w/3-5 AHT meds
5. Change in AOBP SBP by week 6 50mg w/obesity
6. change in AOBP SBP by week 12 from 6 who escalated 50 to 100mg (within-subject analysis)
Exploratory endpoints (8)
- SBP change from baseline to week 12
- % achieving AOBP SBP <130 by week 12
- % with AOBP SBP <130 and DBP <80 by week 6
- % with AOBP SBP <130 and DBP <80 by week 12
- Change in DBP by week 12
- Change in MAP by week 12
- Change in UACR by week 12
- Change in biomarkers from week 0 to 12
Safety Endpoints (4)
- AEs
- change in vitals, PE, or EKG
- change in labs (chem or urinalysis)
- AESI
AESI (8)
- dose change 2/2 hyperkalemia
- dose change 2/2 hyponatremia
- symptomatic hypotension
- Severely elevated BP (>180 or >110)
- dose change 2/2 hypercortisolism (am cortisol >35)
- d/c drug 2/2 hypocortisolism confirmed by ACTH
- overdose of IP or AHT regimen
- modification of IP 2/2 reduction in renal function
Study design
2 week screening
2 week run in (single blind)
12 week DB
Inclusion criteria (11)
- Consent
- 18+
- at screening and randomization: AOBP SBP =135-180 and =65-110. OR
- 2-5 AHT stable for 1 mo prior to screening. 1x has to be thiazide or thiazide like unless given waiver
- HTN for atleast 6 mo prior to screening
- am cortisol 8-10am between 3 and 22 at screening
- BMI >=18 at screening
- arm circ <52cm at screening
- birthcontrol agreement from screening to 28 days after last dose of IP
- compliance with study instructions and scheduled visits
Exclusion criteria
- Pregnant or breastfeeding
- hypersensitivity to IP
- treatment or anticipated treatment with contraindicated meds in timeframe of study
- participation in another study of device or small-molecule within 4 weeks or 6 months (abs) prior to screening
- eGFR <45
- K+ >5.0 at screening or >4.8 at randomization
- Na (corrected for hyperglycemia) <135 at screening.
- hx or recent hyponatremia within 1 year prior to screening
- hospitalization for HTN within 1 year prior to screening
- hx adrenal insuff or abnormal ACTH within 1 year prior to screening
- current, known, or presumed white coat HTN (>20SBP change in clinic compared to home
- current, known, or presumed orthostatic hypotension
- current, known, or presumed autonomic dysfunction
- current or anticipated nightshift worker for >14 or more consecutive days during trial
- previous proven secondary HTN with exception of sleep apnea or PA
- Hx of HF, MI, CVA, TIA within 6 mo prior to screening. Waiver acceptable
- DM w/ A1C >9
- DM w/hypoglycemic event in past 12 mo prior to screening or limited awareness of hypoglycemia
- planned major surgery requiring hosp during study or 4 weeks prior to screening
- hx of malignant neoplasms within 5 years prior to screening except BCC or SCC of skin or previously treated carcinoma in-situ
- no MRA or ENaC
- in opinion or investigator, any other condition that will preclude participation in study
Criteria for up titration (4) @ week 6
AOBP SBP >=130
K <=4.8
Na >=135
eGFR >45 and <25% reduction eGFR from randomization
Sample Size?
detectable difference by mmHg?
assumed standard deviation?
750 IP, 250 placebo
3.7mmHg
14mmHg deviation
