BREAKOUT: A Phase IIb, Multicenter, Open-Label, Prospective Study of Bremelanotide in Diabetic Kidney Disease
Study Details
Study Description
Brief Summary
This is a prospective, open-label trial to assess the efficacy of melanocortin receptor agonist bremelanotide (BMT) when administered with RAAS inhibition therapy after six months in subjects with Type II diabetic nephropathy. After six months of therapy, all subjects will remain in trial for further assessment and undergo a diagnostic renal biopsy to assess the effect of melanocortin therapy on diabetic histopathology at 12 months.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
A total of 45 subjects with biopsy-proven Type II diabetic nephropathy and >1000 mg/gm UP/Cr ratio will be enrolled to receive BMT therapy in addition to their maximum tolerated RAAS inhibition therapy for six months. The subjects' historical medical and laboratory data collected at four timepoints, approximately 24, 18, 12, and 6 months prior to Day 0, will be reviewed and recorded to be used as baseline values.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Subcutaneous Bremelanotide BMT sterile aqueous solution for injection provided as a prefilled syringe, administered by subcutaneous (SQ) injection into the abdomen. |
Drug: Bremelanotide
Bremelanotide is a cyclic, heptapeptide analog of the endogenous peptide alpha melanocortin stimulating hormone (αMSH).
Other Names:
Drug: RAAS inhibition therapy
RAS-acting agents are medicines acting on a hormone system that helps to control blood pressure and the amount of fluid in the body.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- To demonstrate efficacy of subcutaneous BMT used in combination with a subject's maximum tolerated dose of RAAS inhibition therapy to reduce urinary protein and maintain podocyte density and functions in subjects with Type II diabetic nephropathy. [Baseline to after six months of combined therapy (RAAS inhibition therapy plus BMT).]
Proportion of subjects with Type II diabetic nephropathy who achieve a 50% reduction in their urine protein Cr (UP/Cr) ratio after six months of combined therapy (RAAS inhibition therapy plus BMT).inhibition therapy to reduce urinary protein and maintain podocyte density and functions in subjects with Type II diabetic nephropathy after six months.
- To determine the incidence of overall adverse events, related adverse events, a composite of adverse events of special interest, serious adverse events, and the incidence of BMT discontinuation. [Baseline to after six months of combined therapy (RAAS inhibition therapy plus BMT).]
Proportion of subjects with Type II diabetic nephropathy who achieve a 50% reduction in their urine protein Cr (UP/Cr) ratio after six months of combined therapy (RAAS inhibition therapy plus BMT) to determine the incidence of adverse events, related adverse events, adverse events of special interest, serious adverse events and BMT discontinuation.
Secondary Outcome Measures
- To evaluate the efficacy of SQ BMT in combination with RAAS inhibition therapy to achieve partial remission. [>50% from baseline, and to a level < 1000 mg/gm, at six months]
Partial Remission: Proportion of subjects that achieve a reduction in UP/Cr ratios of >50% from baseline, and to a level < 1000 mg/gm, at six months.
- To assess the efficacy of SQ BMT in combination with RAAS inhibition therapy to achieve complete remission. [>30% from baseline at six months]
Clinical Remission: Proportion of subjects that achieve a reduction in UP/Cr ratios of >30% from baseline, at six months
- To measure the efficacy of SQ BMT in combination with RAAS inhibition therapy to achieve a <1.0 ml/min/year drop in eGFR after six months [<1.0 ml/min/year drop in eGFR from baseline to six months]
Proportion of subjects with Type II diabetic Nephropathy receiving maximally tolerated renin-angiotensin (RAAS) blockade that achieves a <1.0 ml/min/year drop in eGFR at six months
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male or female aged between 18 years and 80 years, inclusive, willing, and able to understand the risks of the trial and consents to trial conduct documented by the signing of the trial informed consent form.
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Have a diagnosis of Type II diabetes mellitus in a controlled state (defined as Hemoglobin A1c (HgbA1c) ≤ 12%).
Note: Efforts will be made to enroll subjects with known diabetic retinopathy and diabetic peripheral neuropathy to examine the potential benefits of melanocortin receptor activation outside kidney disorders.
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Have a BMI ≤ 45 kg/m^2.
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Have a diagnosis of Stage I, II, or III diabetic nephropathy, confirmed by renal biopsy within 5 years of Screening.
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Have been on a stable dose of oral diabetic agents or insulin injections for ≥3 months prior to randomization.
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Be on a stable, maximum tolerated dose (as determined by the Investigator) of an angiotensin-converting enzyme (ACE) or angiotensin-receptor blockers (ARB) as primary antihypertensive therapy (titrated to the highest dose to achieve a stable average target blood pressure of <140/90 for ≥1 month prior to randomization).
Note: Modification of ACE-ARB agents after consent will be prohibited. The addition of finerenone or other mineralocorticoid antagonists AFTER giving consent will be prohibited.
Note: Subjects requiring additional medications to achieve the target blood pressure will use antihypertensive agents that have neutral effects on urinary proteinuria (e.g., hydralazine or long-acting dihydropyridine calcium channel blockers, etc.).
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Any subject taking mineralocorticoid receptor antagonists must have been on a stable dose for ≥3 months prior to randomization.
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Any subject taking a medication that the Investigator believes could alter urinary protein or eGFR must agree to maintain a stable dose throughout the study period, including SGLT2 inhibitors.
Note: Insulin and other diabetic agents can be adjusted for glycemic control.
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Have an eGFR by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula ≥20 but <90 ml/min/1.73m^2, with at least two eGFR determinations during the past 24 months.
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Have at least two UP/Cr ratios or 24-hour urine collection of protein with an average UP/Cr ratio of > 1000 mg/gm from the average of two early morning urinary voids obtained three days apart during the 24 months PRIOR to randomization.
Note: Any clinical data available during the two years prior, including additional UP/Cr and eGFR determinations, will be averaged over the two years and used to establish baseline renal function.
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For female subjects:
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Women of childbearing potential (WOCBP) must agree to abstain from heterosexual intercourse or use a highly effective contraceptive(s) (with a failure rate of <1% per year), as described in the protocol, during the treatment and follow-up and for at least 90 days after the last dose of BMT. Female Subjects must agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this 90-day period. Hormonal-based contraception is to be employed for a minimum of 28 days prior to Day 0. The Investigator should evaluate the effectiveness of the contraception method in relation to the dose of the investigational product. Note: Oral hormonal contraceptives should be combined estrogen and progesterone. If a progesterone-only oral contraceptive is used, then a second method of birth control should be used as well.
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Alternatively, a female of non-childbearing potential is defined as:
- Age ≥ 50 years, no menses for at least one year, per subject self-report. ii. Documented hysterectomy, bilateral tubal ligation, or bilateral oophorectomy.
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For male subjects:
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Agree to abstain from heterosexual intercourse or use double barrier protection with condom and spermicide with any WOCBP sexual partner from screening and continuing for at least 30 days after the administration of BMT. Male subjects must also agree not to donate sperm during these 30 days.
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Alternatively, documented sterilization confirmed by the absence of sperm in the ejaculate or ≥ one-year post-operative from vasectomy.
Exclusion Criteria:
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Females who are pregnant or breastfeeding or plan to become pregnant or donate ova during the trial or 30 days after trial participation.
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Has a known allergy or intolerance to AECI, ARB, or melanocortin peptides.
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Patients with a known polymerase chain reaction (PCR) positive result for the human immunodeficiency virus (HIV), hepatitis C and hepatitis B. The decision whether to update the PCR test will be left to the discretion of the Investigator.
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Patients with a known active history of alcohol dependence and/or drug use (with Cannabis exception) will be excluded from the study.
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Has significant medical illnesses that cannot be adequately controlled with appropriate therapy and may obscure toxicity, dangerously alter drug metabolism, or compromise the subject's ability to participate in the trial, as determined by the Investigator.
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Has current or prior receipt of bremelanotide therapy within the past year.
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Has used cyclosporine A, adrenocorticotropic hormones,corticosteroids, immunosuppressants, or cytotoxic agents within the past 6 months.
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Has a known positive serology result for ANA, anti-ds-DNA, RPR, C-ANCA, and P-ANCA.
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Has a solitary kidney (acute kidney injury "AKI" risk) or is on dialysis.
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Has a clinically significant abnormal ECG (QTcF interval >550msec) or in the opinion of the site investigator, has compromising heart failure or other cardiomyopathies.
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Has a known history of diabetic ketoacidosis, diabetic gastroparesis, hyperosmolar states, non-diabetic renal disease, AKI, kidney transplant, pancreatic insulin deficiencies, non-DN glomerular diseases, non-diabetic renal diseases, cancer, recent significant weight change.
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Has symptomatic and clinically significant hypotension or dehydration, as determined by the Investigator.
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Has taken any experimental drug or therapy within 28 days / 5 half-lives of trial treatment or concurrently participating in another clinical trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | California Institute of Renal Research | Chula Vista | California | United States | 91910 |
| 2 | Georgia Nephrology, LLC DBA -GA Nephrology Research Institute | Decatur | Georgia | United States | 30030 |
| 3 | Georgia Nephrology, LLC [DBA] GA Nephrology Research Institute | Lawrenceville | Georgia | United States | 30046 |
| 4 | Brookview Hills Research Associates, LLC | Winston-Salem | North Carolina | United States | 27103 |
| 5 | Prolator Clinical Research Center | Houston | Texas | United States | 77030 |
| 6 | Clinical Advancement Center, PLLC | San Antonio | Texas | United States | 78212 |
Sponsors and Collaborators
- Palatin Technologies, Inc
Investigators
- Study Director: Robert Jordan, Palatin
- Principal Investigator: James Tumlin, MD, Georgia Nephrology Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- BMT-701