E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of cardiovascular and renal disease in patients with chronic kidney disease |
soggetti con diagnosi clinica di malattia renale cronica |
|
E.1.1.1 | Medical condition in easily understood language |
chronic kidney disease |
malattia renale cronica |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001580 |
E.1.2 | Term | Albuminuria |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the change in albuminuria by urinary albumin-to-creatinine ratio (UACR) after treatment with titrated doses of runcaciguat given once daily from baseline to day 57 (+/-3) |
Valutare la variazione dell’albuminuria misurata come rapporto albumina-creatinina urinaria (UACR) dopo il trattamento con dosi titolate di runcaciguat somministrato una volta/die dal basale al giorno 57 (±3) |
|
E.2.2 | Secondary objectives of the trial |
To investigate the overall safety and tolerability of runcaciguat |
Valutare la sicurezza globale e la tollerabilità di runcaciguat |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age
1. Participant must be ≥ 45 of age inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants who have:
• history of any of the following:
- type 2 diabetes mellitus as defined by the American Diabetes Association (on treatment with glucose-lowering medications and/or insulin) for at least 2 years, and/or
- diagnosis of hypertension (defined as systolic blood pressure [BP] values ≥ 140 mmHg and/or diastolic BP values ≥90 mmHg) and on hypertension medication for at least 5 years
• established atherosclerotic cardiovascular disease (e.g. coronary artery disease, peripheral arterial disease, cerebrovascular disease) or heart failure
• a clinical diagnosis of CKD based on all of the following criteria:
- (estimated) glomerular filtration rate (eGFR) ≥ 25 mL/min/1.73 m2 but ≤ 60 mL/min/1.73 m2 (acc. Percentage of decrease in eGFR [CKD EPI])
- persistent high albuminuria defined as urine albumin-to-creatinine ratio [UACR] of between 30 mg/g and 3000 mg/g in 2 first morning void samples (collected at least 1 week apart)
- Stable treatment with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) for the participant maximum tolerated labelled daily dose and otherwise stable antihypertensive treatment both for at least 3 months before randomization, without any adjustments to this therapy for at least 4 weeks prior to randomization.
• Diabetes patients that are on SGLT2-inhibitor (SGLT: sodium glucose transport protein) have to be on stable treatment for at least 3 months before Screening visit. |
(Traduzione in italiano non disponibile -si rimanda alla lista dei Criteri ufficiale inclusa nel protocollo)
Age:
1. Participant must be ≥ 45 of age inclusive, at the time of signing the
informed consent.
Type of Participant and Disease Characteristics:
2. Participants who have:
• history of any of the following:
- type 2 diabetes mellitus as defined by the American Diabetes
Association (on treatment with glucose-lowering medications and/or
insulin) for at least 2 years, and/or
- diagnosis of hypertension (defined as systolic blood pressure [BP]
values ≥ 140 mmHg and/or diastolic BP values ≥90 mmHg) and on
hypertension medication for at least 5 years
• established atherosclerotic cardiovascular disease (e.g. coronary
artery disease, peripheral arterial disease, cerebrovascular disease) or
heart failure
• a clinical diagnosis of CKD based on all of the following criteria:
- (estimated) glomerular filtration rate (eGFR) ≥ 25 mL/min/1.73 m2
but ≤ 60 mL/min/1.73 m2 (acc. Percentage of decrease in eGFR [CKD
EPI])
- persistent high albuminuria defined as urine albumin-to-creatinine ratio [UACR] of between 30 mg/g and 3000 mg/g in 2 first morning void
samples (collected at least 1 week apart)
- Stable treatment with angiotensin-converting enzyme inhibitor (ACEi)
or angiotensin-receptor blocker (ARB) for the participant maximum
tolerated labelled daily dose and otherwise stable antihypertensive
treatment both for at least 3 months before randomization, without any
adjustments to this therapy for at least 4 weeks prior to randomization.
• Diabetes patients that are on SGLT2-inhibitor (SGLT: sodium glucose
transport protein) have to be on stable treatment for at least 3 months
before Screening visit.
|
|
E.4 | Principal exclusion criteria |
Medical Conditions
1. Known non-diabetic and non-hypertension related renal diseases as autosomal dominant polycystic kidney disease, bilateral clinically relevant renal artery stenosis, lupus nephritis, or ANCA-associated vasculitis, IgA nephropathy without hypertension, or any other secondary glomerulonephritis
2. Clinical diagnoses of heart failure and persistent symptoms (New York Heart Association (NYHA class III - IV)
3. Uncontrolled hypertension indicated by >160 mmHg systolic BP or ≥100 mmHg diastolic BP
4. History of secondary hypertension (i.e., renal artery stenosis, primary aldosteronism, or pheochromocytoma).
5. Stroke, transient ischemic cerebral attack, acute coronary syndrome, or hospitalization for worsening heart failure, in the last 3 months prior to the planned randomization
6. Dialysis for acute renal failure within the previous 6 months prior to the planned randomization
7. Renal allograft in place or a scheduled kidney transplant within the next 18 weeks (being on a waiting list does not exclude the subject)
8. Hepatic insufficiency classified as Child-Pugh B or C or other significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis as indicated by e.g. aspartate aminotransferase [AST] or Alanine aminotransferase [ALT] >3x upper limit of norm [ULN]).
9. Active malignancy other than treated squamous cell, carcinoma in situ, or basal cell carcinoma of the skin
Prior/Concomitant Therapy
10. Non diabetic patients treated with SGLT-2 inhibitors
11. Combination use of ACEi and ARB within 3 months prior to randomization
12. Concomitant therapy with nitrates, PDE5 inhibitors including non-specific inhibitors (e.g. dipyridamole and theophylline), soluble guanylate cyclase [sGC] stimulators, renin inhibitors (within 4 weeks prior to randomization)
13. Participation in another clinical study or treatment with another investigational product 90 days prior to randomization
14. Previous randomization in this study
Diagnostic Assessments
15. HbA1c >11%
|
(Traduzione in italiano non disponibile -si rimanda alla lista dei Criteri ufficiale inclusa nel protocollo)
Medical Conditions
1. Known non-diabetic and non-hypertension related renal diseases as
autosomal dominant polycystic kidney disease, bilateral clinically
relevant renal artery stenosis, lupus nephritis, or ANCA-associated
vasculitis, IgA nephropathy without hypertension, or any other
secondary glomerulonephritis
2. Clinical diagnoses of heart failure and persistent symptoms (New York
Heart Association (NYHA class III - IV)
3. Uncontrolled hypertension indicated by >160 mmHg systolic BP or ≥
100 mmHg diastolic BP
4. History of secondary hypertension (i.e., renal artery stenosis, primary
aldosteronism, or pheochromocytoma).
5. Stroke, transient ischemic cerebral attack, acute coronary syndrome,
or hospitalization for worsening heart failure, in the last 3 months prior
to the planned randomization
6. Dialysis for acute renal failure within the previous 6 months prior to
the planned randomization
7. Renal allograft in place or a scheduled kidney transplant within the
next 18 weeks (being on a waiting list does not exclude the subject)
8. Hepatic insufficiency classified as Child-Pugh B or C or other
significant liver disease (e.g., acute hepatitis, chronic active hepatitis,
cirrhosis as indicated by e.g. aspartate aminotransferase [AST] or
Alanine aminotransferase [ALT] >3x upper limit of norm [ULN]).
9. Active malignancy other than treated squamous cell, carcinoma in
situ, or basal cell carcinoma of the skin
Prior/Concomitant Therapy
10. Non diabetic patients treated with SGLT-2 inhibitors
11. Combination use of ACEi and ARB within 3 months prior to
randomization
12. Concomitant therapy with nitrates, PDE5 inhibitors including nonspecific
inhibitors (e.g. dipyridamole and theophylline), soluble
guanylate cyclase [sGC] stimulators, renin inhibitors (within 4 weeks prior to randomization)
13. Participation in another clinical study or treatment with another
investigational product 90 days prior to randomization
14. Previous randomization in this study
Diagnostic Assessments
15. HbA1c >11%
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Mean change in UACR from baseline to the average of multiple time points during treatment |
Variazione media dell’UACR dal basale alla media di più momenti temporali durante il trattamento tra la Visita 4 (Giorno 22±2) e la Visita 7 (Giorno 57±4), valutata sulla popolazione per-protocol (PPS) utilizzando un approccio a modelli misti con il basale come covariata. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline up to day 57 (± 3) |
da basele fino al Giorno 57 (± 3) |
|
E.5.2 | Secondary end point(s) |
Number of subjects with treatment emergent adverse event (TEAE)
Number of subjects with early discontinuations |
Sicurezza e tollerabilità in base agli AE e al tasso di interruzione dello studio. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Number of subjects with TEAE: From first treatment administration up to end of follow up (Day 87±7)
Number of subjects with early discontinuations: From first treatment administration up to end of treatment (Day 57±3)
|
Per quanto riguarda il numero di pazienti con TEAE: dalla prima somministrazione alla fine del follow up (giorno 87±7)
Per quanto riguarda il numero di pazienti con “early discontinuations”: dalla prima somministrazione alla fine del trattamento (giorno 57±3)
|
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Bulgaria |
Denmark |
Finland |
Germany |
Israel |
Italy |
Poland |
Spain |
Sweden |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as the date of the last visit of the last participant in the study globally. |
LPLV |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 10 |