Uncontrolled Hypertension in Patients with Chronic Kidney Disease

A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-Group, Dose-Ranging Study to Evaluate CIN-107 for the Treatment of Patients With Uncontrolled Hypertension and Chronic Kidney Disease. 

Inclusion Criteria

Patients who meet all of the following criteria will be eligible to participate in the study:

  1. Is an adult male or female patient ≥18 years of age;
  1. Has a mean seated SBP ≥140 mmHg at Screening (Visit 1), Visit 2, and Visit 3;

Note: Patients with mean seated SBP ≥130 mmHg may be eligible if diabetic.

Note: Mean seated SBP is defined as the average of 3 seated SBP measurements at any single clinical site visit.

  1. Has a prior diagnosis of mild-to-severe CKD, defined as eGFR (based on the chronic kidney disease epidemiology [CKD-EPI] equation) of 25 to 75 mL/min/1.73 m2, inclusive, at Visit 1;

Note: To ensure patients with moderate and severe renal impairment will be represented, the number of patients with an eGFR 60 and < 75 mL/min/1.73 m2 will be capped at 45 (approximately 15% of the total population.)

  1. Has a UACR ≥100 mg/g (≥11.3 mg/mmol) in at least 2 out of 3 measurements based on first urine collected in the morning on consecutive days during the Screening Period;
  1. Is currently taking an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) at the patient’s maximum tolerated daily dose, based on Investigator judgment, for >4 weeks prior to Visit 1;

Note: Taking additional antihypertensive agents is permitted except an MRA or a potassium-sparing diuretic (eg, triamterene, amiloride, etc.).

  1. If taking a sodium-glucose cotransporter-2 (SGLT2) inhibitor at Screening (Visit 1), the regimen must be stable for a period of at least 8 weeks before Visit 1 and be expected to remain at a stable dose over the study period;

Note: It is expected that patients not currently taking an SGLT2 inhibitor at Screening (Visit 1) will not initiate this class of medication during the entire Study Period.

  1. Is willing to be compliant with the contraception and reproductive restrictions of the study as follows:

Female patients of childbearing potential (ie, ovulating, pre-menopausal, and not surgically sterile) must have a documented negative pregnancy test at Visit 1 and the Randomization Visit (Visit 3); and

Female patients of childbearing potential must use a highly effective method of contraception (ie, <1% failure rate) from Day 1 through 30 days after the last administration of study drug.

Note: Acceptable methods of contraception for female patients of childbearing potential enrolled in the study include the following:

Surgical sterilization (tubal ligation);

Intrauterine device for at least 12 weeks before Visit 1;

Hormonal contraception (oral, implant, injection, ring, or patch) for at least 12 weeks before Visit 1; or

Diaphragm used in combination with spermicide.

Post-menopausal women must have not had menstrual bleeding for at least 1 year before initial dosing and either be >60 years or have an elevated follicle-stimulating hormone level >40 mIU/mL at Visit 1;

  1. Is able and willing to give informed consent for participation in the study.
  1. After the mandatory run-in period of 2 weeks, investigators must confirm the patient’s BP and UACR measurements still meet the eligibility criteria.

 

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from participation in the study:

  1. Have a documented diagnosis of type 1 diabetes;
  1. Are not willing or not able to discontinue a MRA or a potassium-sparing diuretic as part of an existing antihypertensive regimen;

Note: Patients taking an MRA or a potassium-sparing diuretic (eg, triamterene, amiloride, etc.) as an antihypertensive agent must be willing to discontinue this agent for study eligibility. The potassium-sparing diuretic may be discontinued and replaced with a non-potassium-sparing diuretic. All patients who remain on a stable regimen of antihypertensive agents, including a non-potassium-sparing diuretic, for at least six weeks, will be eligible to enter the single-blind Run-in. If the subject discontinues their prior MRA or potassium-sparing diuretic and/or initiates a new antihypertensive for study eligibility, they should remain on a stable regimen of antihypertensive agents for at least six weeks and will have an extended screening period of 9 weeks from signing of informed consent to randomization (V3).

  1. Have a single occurrence of mean seated SBP >180 mmHg or DBP >110 mmHg during the Screening Period (if such a BP is recorded during the Screening Period, the patient may attend an Interim Visit for an additional BP measurement and reassessment of Inclusion/Exclusion Criteria);

Note: Mean seated BP is defined as the average of 3 measurements obtained at any 1 clinical site visit. If the patient missed the regularly scheduled antihypertensive medication(s) prior to the visit (Visits 1 or 2), 1 BP re-test is allowed ≥2 hours after taking the medication(s), on the following day, or later after reestablishing the regularly scheduled antihypertensive regimen.

  1. Has a body mass index (BMI) >50 kg/m2 at Visit 1;
  1. Has documented bilateral clinically relevant renal artery stenosis of ≥70%; if the imaging evidence is met, the subject should be excluded since hypertension itself could be considered ‘clinically relevant’. Suspected or non-documented renal artery stenosis is not excluded.
  1. Has had dialysis for acute kidney injury/acute renal failure within 12 weeks prior to the Screening Period, or has a planned dialysis or kidney transplantation during the course of the study;
  2. Has known documented chronic heart failure New York Heart Association Class III or Class IV and/or hospitalization for heart failure within 6 months of Visit 1;
  3. Has had a stroke, transient ischemic attack, hypertensive encephalopathy, acute coronary syndrome, or hospitalization for heart failure within 6 months of Visit 1;
  1. Has known current severe left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy and/or severe aortic valvular disease, diagnosed from a prior echocardiogram or another imaging study;
  1. Has a planned coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) or any major surgical procedure during the study;
  2.  Has had PCI, CABG, other major cardiac surgery (eg, valve replacement), or peripheral arterial bypass surgery within 6 months of Visit 1;
  1. Has had a prior solid organ transplant or cell transplant;
  1. Is expected to receive or is receiving any of the exclusionary drugs such as strong inducers of cytochrome P450 3A, chronic use (medication is taken more than 3 times a week for more than 3 months) of non-steroidal anti-inflammatory drugs, spironolactone/ eplerenone, and/or chronic use of systemic steroids;
  1. Has a known hypersensitivity to any of the following:

CIN-107 or drugs of the same class; or

Excipients in CIN-107 or drugs of the same classes.

  1. Has received immunotherapy for treatment of CKD within 6 months of Visit 1 or expects to receive immunotherapy for treatment of CKD during participation in the study;
  1. Has any clinically relevant medical or surgical conditions including unstable conditions and/or conditions requiring regular transfusion or treatment with systemic immunosuppressants, including corticosteroids that, in the opinion of the Investigator, would put the patient at risk by participating in the study;
  1. Has evidence of any of the following at Visit 1 (1 retest is allowed):
  • White blood cell count >15 × 109/L or absolute neutrophil count <1 × 109/L;
  • Serum potassium <3.5 mEq/L;

Note: Patients with a serum potassium level below normal range may continue in the study if the Investigator elects to correct the serum potassium level with supplementation and offers to manage the condition.

  • Serum potassium >5.0 mEq/L;
  • Serum sodium <135 mEq/L;
  • Serum aspartate aminotransferase or alanine aminotransferase >3 × upper limit of normal (ULN); or
  • Total bilirubin >2 × upper limit of normal (ULN), unless due to Gilbert’s syndrome.
  • Estimated GFR is <25 or > 75 mL/min/1.73 m2
  1. Has uncontrolled diabetes with glycosylated hemoglobin >10.5% at Visit 1.
  2. Is positive for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen, or hepatitis C virus ribonucleic acid (RNA);
  1. Has typical consumption of >14 alcoholic drinks weekly;

Note: 1 drink of alcohol is equivalent to ½ pint of beer (285 mL), 1 glass of spirits (25 mL), or 1 glass of wine (125 mL).

  1. Has participated in another clinical study involving any investigational drug within 30 days prior to Visit 1, or plans to participate in another clinical study within 30 days of discontinuation of study drug;
  1. Has received experimental therapy for disease intervention with a small molecule within 30 days of Visit 1 or 5 half-lives, whichever is longer, or received experimental therapy with a large molecule within 90 days of the Visit 1 or 5 half-lives, whichever is longer;

Note: Vaccinations, including those for COVID-19, will not be exclusionary.

  1. Is pregnant, breastfeeding, or planning to become pregnant during the study; or
  1. Is considered by the Investigator, after reviewing medical and psychiatric history, physical examination, and laboratory evaluations, to be unsuitable for any other reason that may either place the patient at increased risk during participation or interfere with the interpretation of the study outcomes. History of COVID-19 infection, in of itself, is not an exclusionary criterion unless the subject is subsequently considered unsuitable for the study based on criteria above.

 

Withdrawal Criteria

Patients may withdraw consent or requests discontinuation from the study participation for any reason. The site staff should make every effort to complete the assessments scheduled for the Early Termination visit. The reason for patient withdrawal must be documented in the electronic case report form (eCRF). The Sponsor or the regulatory authority may terminate the study.

Dosing may be discontinued for any of the following reasons:

  • The patient has a mean seated BP >170/105 mmHg at 2 separate occasions during the Double-Blind Treatment Period;
  • Occurrence of any medical condition or circumstance that exposes the patient to substantial risk and/or does not allow the patient to adhere to the requirements of the protocol;
  • Pregnancy;
  • Requirement of prohibited concomitant medications;
  • Patient failure to comply with protocol requirements or study-related procedures.

If a patient withdraws dosing prematurely from the study due to the above criteria, the site staff should make every effort to schedule the remaining protocol specified visits and retrieve as much safety and efficacy data as possible.

In the case of a patient lost to follow-up, attempts to contact the patient must be made and documented in the patient’s medical records. Patients who discontinue participation in the study will not be replaced.

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