The main objectives of the trial are to demonstrate the effectiveness of BI 685509 and to characterize the dose-response relationship for BI 685509 in patients with DKD by assessing 3 doses and placebo.
ID
Source
Brief title
Condition
- Diabetic complications
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline in log transformed Urine Albumin Creatinine Ratio (UACR)
measured in 10-hour urine after 20 weeks of trial treatment.
Secondary outcome
- Change from baseline in log transformed UACR measured in First Morning Void
urine after 20 weeks of trial treatment.
- Proportion of patients achieving UACR decreases in 10-hour urine of at least
20% from baseline after 20 weeks of trial treatment.
- Proportion of patients achieving UACR decreases in First Morning Void urine
of at least 20% from baseline after 20 weeks of trial treatment.
Background summary
Diabetes is a globally prevalent disease that is expected to grow exponentially
over the coming decades. Amongst the complications of diabetes, the development
of diabetic kidney disease (DKD), also known as diabetic nephropathy, may be
the most devastating with respect to patients* quality of life and survival.
For example, as glomerular filtration rate (GFR) declines, there is a linear
increase in mortality, with 2- to 5-fold increases in patients with GFR < 45
mL/min/1.73 m² compared to patients with a GFR > 60 mL/min/1.73 m². Declining
renal function is associated with an increasing risk for the occurrence of
coronary heart disease, stroke and heart failure. DKD is the leading cause of
kidney damage and end-stage renal disease (ESRD), accounting for > 40% of
dialysis patients. The 5 year survival rate of a dialysis patient is 35% and
only 25% in
diabetic dialysis patients.
Soluble guanylate cyclase (sGC) is activated by nitric oxide (NO) to generate
cyclic guanosine monophosphate (cGMP). Sufficient levels of cGMP within the
kidney are crucial for proper endothelial function in the vascular bed. This
pathway is impaired in patients with diabetes due to less NO production, more
scavenging of available NO by superoxide, and a loss of responsiveness to NO
due to oxidative stress. The resulting endothelial dysfunction is proposed to
be one of the underlying mechanisms for renal impairment in patients with
diabetes.
In addition to BI 685509, at least one other sGC activator (runcaciguat) is
currently in phase II development.
The aim of this trial is to investigate the efficacy, safety, tolerability, PK
and PD of three oral doses of BI 685509 over 20 weeks in male and female
patients with DKD as adjunctive to ACEi or ARB treatment plus local standard of
care according to respective guidelines. The results of this trial will be
crucial for the decision about further development of BI 685509 and will
support the dose selection for future trials.
Study objective
The main objectives of the trial are to demonstrate the effectiveness of BI
685509 and to characterize the dose-response relationship for BI 685509 in
patients with DKD by assessing 3 doses and placebo.
Study design
Patients will be enrolled (screened) in the trial once they have signed the
informed consent. They will undergo a screening period of up to 2 weeks from
the time of informed consent. After their eligibility has been confirmed at
screening, patients will continue in a 2-week baseline run in period. Patients
who successfully complete the screening and baseline run-in period and meet the
inclusion / exclusion criteria will be randomised equally into one of three
parallel dose groups, and in each dose group to treatment for 20 weeks either
with BI 685509 or matching placebo in a 3:1 ratio.
After end of treatment patients will continue with a 4-week follow-up with
further urine and blood sampling. Beyond analysis for safety, urine and blood
samples in this trial will serve for biomarker analysis including UACR and
eGFR.
Intervention
All patients will start on 1 mg TID BI 685509 or matching placebo. If the
medication is tolerated, up-titration to 2 mg TID BI 685509 or matching placebo
will occur after 2 weeks for patients in dose groups 2 and 3, and up-titration
to 3 mg TID BI 685509 or matching placebo will occur after another 2 weeks for
patients in dose group 3.
Patients will receive 20 weeks of treatment in total, which is expected to be
the duration required to obtain stable effects.
Study burden and risks
- Worsening of diabtic kidney disease if patient is in placebo group
- Patient may experience side effects or adverse events of the study drug
- Patient may experience discomfort due to the procedures and measurements
during the study
- Additional procedures and measurements will be performed (outside SoC), as
described in the protocol (v4.0 / 13 Oct 2021)
- Participating in the study will take extra time
- Patient will be asked to complete diaries
- Patient needs to adhere to the study schedule
Comeniusstraat 6
Alkmaar 1817MS
NL
Comeniusstraat 6
Alkmaar 1817MS
NL
Listed location countries
Age
Inclusion criteria
1. Signed and dated written informed consent in accordance with ICHGCP and
local legislation prior to admission to the trial.
2. Male or female patients aged >= 18 years at time of consent.
3. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) >=
20 and < 90 mL/min/1.73 m2 at Visit 1 by central laboratory analysis. eGFR must
remain >= 20 mL/min/1.73 m2 after Visit 1 up to the start of Visit 3, measured
by central or any local laboratory analysis.
4. UACR >= 200 and < 3,500 mg/g in spot urine (midstream urine sample) by
central laboratory analysis at Visit 1.
5. Treatment with the highest tolerated dose of either ACEi or ARB (but not
both together), and stable dose for >= 4 weeks before Visit 1 with no planned
change of the therapy during the trial.
6. If the patient is taking any of the following medications they should be on
a stable dose at least 4 weeks prior to visit 1 until start of treatment, with
no planned change of the therapy during the trial: anti hypertensives, NSAIDs,
endothelin receptor antagonists, systemic steroids or SGLT2 inhibitors.
7. Patients with stable type 1 or type 2 diabetes mellitus, diagnosed before
informed consent. Treatment (including SGLT2 inhibitor and/or GLP1 receptor
agonist) should have been unchanged or changes deemed minor (according to
investigator's judgement) within 4 weeks before Visit 1 and until start of
trial treatment.
8. Glycated Haemoglobin (HbA1c) < 10.0% at Visit 1 measured by the central
laboratory.
9. Seated SBP >= 110 and <= 160 mmHg and DBP >= 65 and <= 110 mmHg at Visit 1 and
optimized anti-hypertensive treatment according to local standard of care and
investigator's judgement.
10. Body Mass Index (BMI) >= 18.5 and < 50 kg/m2 at Visit 1.
11. Male patients able to father a child must be willing to use condoms if
their sexual partner is a Women of child-bearing potential (WOCBP). WOCBP must
be ready and able to use highly effective methods of birth control per ICH M3
(R2). Such methods should be used
throughout the trial.
Exclusion criteria
1. Treatment with Renin Angiotensin Aldosterone System (RAAS) interventions
(apart from either ACEi or ARB), phosphodiesterase inhibitors, nitrates,
sGC-stimulators/activators (other than trial
treatment) or any other restricted medication (including OATP1B1/3 inhibitors,
UGT inhibitors/inducers) as provided in the Investigator Site File (ISF) within
4 weeks prior to visit 1 and throughout screening and baseline run-in. Patients
who must or wish to continue the intake of
restricted medications (see section 4.2.2.1) or any drug considered likely to
interfere with the safe conduct of the trial are also excluded.
2. Any clinically relevant laboratory value from screening until start of trial
treatment, which in the investigator's judgement puts the patient at additional
risk.
3. Biopsy or otherwise confirmed non-diabetic chronic kidney disease, or
non-diabetic chronic kidney disease in the opinion of investigator, e.g.,
Autosomal Dominant Polycystic Kidney Disease (ADPKD), uncontrolled lupus
nephritis. The presence of a hypertensive etiology does not need to be excluded
unless it is evident this is the only cause for the CKD.
4. Any immunosuppression therapy or immunotherapy in the last 3 months prior to
visit 1 and throughout screening and baseline run-in (except prednisolone <=10
mg or equivalent).
5. Acute kidney injury (AKI) according to the Kidney Disease: Improving Global
Outcomes (KDIGO) definition in the 30 days prior to Visit 1 until the start of
trial treatment.
6. Planned start of chronic renal replacement therapy during the trial or end
stage renal disease before start of trial treatment.
7. Known history of moderate or severe symptomatic orthostatic dysregulation as
judged by the investigator before start of trial treatment.
8. The patient has an active infection with SARS-CoV-2 (or is known to have a
positive test) from screening until randomisation.
9. Medical history of cancer or treatment for cancer in the last two years
prior to Visit 1 (except appropriately treated basal cell carcinoma of the
skin, in situ carcinoma of uterine cervix, and prostatic cancer of low grade
[T1 or T2]).
10. Major surgery (investigator's judgement) planned during the trial.
11. History of clinically relevant allergy/ hypersensitivity that would
interfere with trial participation including allergy to investigational
product/ placebo or its excipients (e.g. lactose monohydrate - see
Investigator Brochure)
12. Any other medical condition that in the investigator's opinion poses a
safety risk for the patient or may interfere with the trial objectives.
13. Previous randomisation in this trial.
Further criteria apply.
[...]
17. QTcF-interval > 450 ms in men or > 470 ms in women at any time from
screening (Visit 1) until start of treatment.
18. A family history of long QT syndrome.
19. Concomitant use of therapies with a known risk of Torsade de Pointes at
screening (Visit 1) and throughout screening and baseline run-in or planned
initiation of such therapies during the trial.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-002929-28-NL |
| CCMO | NL76610.056.21 |