Primary Objectives:* To determine the efficacy of daily oral DP13 treatment (all dose arms combined) to decrease the plasma aldosterone-to-renin ratio (ARR) from baseline in patients with primary aldosteronism (PA)* To determine the efficacy of…
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Brief title
Condition
- Other condition
Synonym
Health condition
Hormonal diseases
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Change in the plasma aldosterone-to-renin ratio (ARR) from baseline (Day 1)
to the end of the 8-week daily oral DP13 treatment period (Day 56) for all dose
arms combined
* Change in mean 24-hour ambulatory systolic blood pressure (aSBP) from
baseline (Day 1) to the end of the 8-week daily oral DP13 treatment period (Day
56) for all dose arms combined
Secondary outcome
* Occurrence of treatment-emergent adverse events (TEAE) and serious adverse
events (SAE) over the entire study duration
* Change in systolic blood pressure (oSBP) from baseline (Day 1) to the end of
the 8-week daily oral DP13 treatment period (Day 56) for all dose arms combined
* Change in the plasma ARR from baseline (Day 1) to biweekly visits (week 2,
week 4, week 6) and to the end of the 8-week daily oral DP13 treatment period
(Day 56) in each individual dose arm
* Change in 24-hour aSBP from baseline (Day 1) to the end of the 8-week daily
oral DP13 treatment period (Day 56) in each individual dose arm
* Change in oSBP from baseline (Day 1) to biweekly visits (week 2, week 4, week
6) and to the end of the 8-week daily oral DP13 treatment period (Day 56) in
each individual dose arm
Background summary
Please refer to the paragraph 1.2 of the protocol
Dysregulation of the mechanisms regulating aldosterone biosynthesis results in
primary aldosteronism (PA); a disorder characterized by elevated plasma
aldosterone concentrations (PAC) and low plasma renin activity (PRA) levels,
hypertension, often hypokalaemia and vascular fibrosis. The two major causes of
PA are unilateral aldosterone producing adenoma (APA) and bilateral adrenal
hyperplasia (BAH), accounting for approximately 95% of all PA cases. In both
forms, aldosterone production is autonomous and not or hardly suppressible by
physiologic stimuli. Potassium channel defects have been identified in APA
leading to sustained calcium signalling and aldosterone production independent
of angiotensin II or potassium regulation. Occurrence of aldosterone-producing
cell clusters or micronodules and genetic defects are proposed to sustain
CYP11B2 activity in bilateral adrenal hyperplasia.
The Endocrine Society clinical practice guidelines for diagnosis of PA
recommend the determination of the aldosterone-to-renin ratio (ARR) as the most
reliable test because the ratio is less affected by diurnal and postural
variations (Funder et al., J Clin Endocrinol Metab 2016). The variability of
the ARR as an initial detection system is reduced practically if guideline
recommendations for patient preparation are followed and technically if common
units for PAC (ng/dL) and PRA (ng/mL per h) and assay systems (specified
immunoassay) are used. The ARR is hence very sensitive but not very specific
for the diagnosis of PA without the subsequent demonstration of at least partly
autonomous, i.e. angiotensin II-independent aldosterone production. Angiotensin
II can be removed with the intravenous saline loading test that leads to volume
expansion and renin suppression or with the captopril challenge test to inhibit
acutely angiotensin-converting enzyme. Likewise, the variability of the
confirmatory aldosterone suppression test is reduced with standardized
preparatory and technical procedures.
Autonomous aldosterone production, independent of renin activity, characterizes
patients with PA and their higher risk for cardiovascular morbidity and
mortality compared to patients with essential hypertension. Mineralocorticoid
receptor (MR) antagonists are the recommended medical therapy for patients with
PA. A retrospective cohort study analysed whether MR antagonist treatment
effectively reduces events (stroke, heart failure, myocardial infarction) for
patients with PA (Hundemer et al., Lancet Diabetes Endocrinol 2017). The
incidence of cardiovascular events and mortality were higher in patients with
PA treated with MR antagonists compared to age- and blood pressure-matched
essential hypertensives. However, the excess risk was limited to patients whose
PRA remained suppressed (<1 ng/mL per h). Patients who tolerated higher MR
antagonist doses had unsuppressed PRA (>1 ng/mL per h) and no significant
excess risk for events. The authors advocated that PA patients be medically
adjusted not only to blood pressure control but also to raised renin levels.
Once daily intake of DP13 capsules by healthy volunteers led to a
dose-dependent decrease of PAC and concomitant increase of PRA, hence a
reduction in the ARR compared to placebo treatment. In addition, DP13
selectively suppressed aldosterone production without affecting cortisol
secretion upon ACTH-stimulation. Placebo-treated volunteers responded hereby
with PAC levels that are typically seen in patients with PA (DP13 *
Investigator Brochure 2019). Therefore, once daily administration of DP13
capsules to patients with PA is expected to lower the plasma ARR by both
decreasing PAC and increasing PRA. In response, the lowering of the ARR is
expected to translate into a lower ambulatory systolic blood pressure within an
8-week treatment period.
Study objective
Primary Objectives:
* To determine the efficacy of daily oral DP13 treatment (all dose arms
combined) to decrease the plasma aldosterone-to-renin ratio (ARR) from baseline
in patients with primary aldosteronism (PA)
* To determine the efficacy of daily oral DP13 treatment (all dose arms
combined) to reduce 24-hour ambulatory systolic blood pressure (aSBP) from
baseline in patients with PA
Secondary Objectives:
* To determine the safety and tolerability of DP13 treatment in patients with PA
* To determine the efficacy of daily oral DP13 treatment (all dose arms
combined) to reduce office systolic blood pressure (oSBP) from baseline in
patients with PA
* To determine the efficacy of daily oral DP13 treatment to decrease the plasma
ARR from baseline in each individual dose arm
* To determine the efficacy of daily oral DP13 treatment to reduce 24-hour aSBP
from baseline in each individual dose arm
* To determine the efficacy of daily oral DP13 treatment to reduce oSBP from
baseline in each individual dose arm
* To determine the dose-dependent efficacy of daily oral DP13 treatment to
decrease the ARR from baseline in patients with PA
* To determine the dose-dependent efficacy of daily oral DP13 treatment to
reduce 24-hour aSBP from baseline in patients with PA
* To determine the dose-dependent efficacy of daily oral DP13 treatment to
reduce oSBP from baseline in patients with PA
Exploratory Objectives:
* To determine the recovery of the plasma ARR after discontinuation of daily
DP13 treatment in patients with PA in all dosage arms combined and in each
individual dosage arm
* To determine the recovery of the oSBP after discontinuation of daily oral
DP13 treatment in patients with PA in all dosage arms combined and in each
individual dosage arm
* To determine the dose-dependent effects of daily oral DP13 treatment on mean
diurnal (day and night) ambulatory systolic and diastolic ambulatory blood
pressure (aSBP/aDBP) in patients with PA
* To determine the dose-dependent efficacy of daily oral DP13 treatment to
decrease urinary aldosterone excretion from baseline values in patients with PA
* To determine the dose-dependent efficacy of daily oral DP13 treatment to
raise blood potassium values from baseline in patients with PA
* To determine the steady-state pharmacokinetics of daily oral DP13 treatment
in patients with PA
Study design
DP13C201 is a multi-centre, randomised, double-blind, baseline- and
withdrawal-controlled study with single-blind placebo run-in and withdrawal
periods. The start of the study is defined as the date the study-specific
informed consent form (ICF) is signed by the first eligible study participant.
The end of the study is defined as the date the last patient completes the
study procedures including any follow-up visits, i.e. last patient last visit.
DP13C201 is a dose range-finding study with three parallel groups of 12
patients each treated with DP13. The treatment effects are baseline- and
withdrawal-controlled at the study start and study end, respectively.
Intervention
* DP13 and placebo capsule intake once daily in the morning
* Physical examination, including weight and blood pressure measurements
* Electrocardiograms (ECG) recordings
* Blood samplings
* Urine collections
* Spot tests on urine
* Urine pregnancy tests
Study burden and risks
The anticipated benefits of treating PA patients with DP13 may include:
* Targeted suppression of uncontrolled and excessive aldosterone secretion at
the rate-limiting step in the adrenal glands addressing the principal etiologic
basis of the disease
* Correction of aldosterone-mediated hemodynamic changes leading to
hypertension, volume retention, hypokalaemia and suppressed renin
* Higher target selectivity and therefore better tolerability and improved
compliance over the standard of care medical therapy, spironolactone
* Suitable for mild to moderately renal impaired patients due to limited renal
elimination of compound and metabolites
* Dose-dependent linear pharmacokinetic and pharmacodynamic properties without
indication for drug accumulation or drug tolerance over time
* Convenient once daily oral administration of neutral tasting capsules without
known susceptibility for metabolic drug-drug interactions
The potential risks for PA patients on DP13 treatment may include:
* Development of hyperkalaemia
* Incidence of headaches, dizziness, orthostasis, hypotension
* Abdominal discomforts
Overall, the clinical phase I profile of DP13 supported by the safety history
of the previously developed racemic parent compound suggests that the
anticipated therapeutic benefits provided by DP13 outweigh the potential safety
risks.
Haltli 6
Walchwil 6318
CH
Haltli 6
Walchwil 6318
CH
Listed location countries
Age
Inclusion criteria
Patients will be required to satisfy all of the following eligibility criteria:
1. Patients with a guideline-recommended diagnosis of PA consisting of:
1.1. ARR *40 derived from a PAC *15 ng/dL and a PRA <1.0 ng/mL/h; an ARR *3.7
is derived with PRC <15 mU/L instead of PRA as denominator
and
1.2. PAC >7.0 ng/dL after a 4-hour infusion of 2 litres 0.9% saline (saline
load suppression test) or instead if clinically justified for risk of volume
expansion ARR>30 and PAC >11 ng/dL (respectively ARR>2.4 with PRC in mU/L
instead of PRA as denominator) after 2 hours of an oral intake of 50 mg
captopril
and
1.3. determined within <1 year of study enrolment
2. Patients with PA per above criteria and
2.1. sitting office systolic blood pressure (oSBP) >145 mmHg
and if applicable
2.2. in presence of non-interfering hypertension control therapy consisting of
doxazosin (1 * 8 mg QD) as first-line medication and, if necessary, only
verapamil slow release (40 * 120 mg BID) or diltiazem (slow-release 90 - 360 mg
daily) or amlodipine (2.5 * 10 mg QD) at adjusted and fixed doses
3. Patients with PA per above criteria will have a:
3.1. estimated glomerular filtration rate (eGFR) *45 mL/min/1.73 m2 using the
MDRD-4 GFR equation: GFR <= 175 x [serum creatinine (mg/dL)]-1.154 x (age)-0.203
x f*
*f<=1.000 for men; f<=0.742 for women; the formula is further multiplied by
factor 1.210 for black skinned patients
3.2. body mass index (BMI) between 18 and 34 kg/m2, inclusive
3.3. body weight between 40 and 110 kg, inclusive
4. Patients with PA per above criteria will be:
4.1. female or male patients between 18 and 65 years of age, inclusive
4.2. able to provide voluntary informed written consent to study enrolment
Exclusion criteria
Patients will be excluded from the study if they satisfy any of the following
criteria:
1. Patients with PA and:
1.1. treated with spironolactone within 2 months of enrolment
1.2. hyperkalaemia of >5.0 mmol/L
1.3. prolonged QT intervals with QTc of >500 msec using Bazett*s formula
2. Patients with PA and:
2.1. sitting office systolic office blood pressure (oSBP) >190 mmHg
and/or
2.2. sitting office diastolic office blood pressure (oDBP) >110 mmHg
and if applicable
2.3. in presence of non-interfering hypertension control therapy consisting of
doxazosin (1 * 8 mg QD) as first-line medication and, if necessary, only
verapamil slow release (40 * 120 mg BID) or diltiazem (slow-release 90 - 360 mg
daily) or amlodipine (2.5 * 10 mg QD) at adjusted and fixed doses
3. Patients with PA who will not consent to special contraception measures
during the entire study period, specifically
3.1. female patients not withdrawing oral contraceptives >2 weeks prior to
enrolment
3.2. female patients not using intrauterine devices (IUD), diaphragm, sponge
with spermicide
3.3. male patients not using condoms and not refraining from sperm donation
4. Patients with PA and a medical history of:
4.1. cerebro- and cardiovascular events (stroke, myocardial infarction,
percutaneous transluminal coronary angioplasty, long QT syndrome, Brugada
syndrome, acute heart failure) within 6 months of study enrolment
4.2. gastrointestinal tract surgeries or malabsorption syndromes
4.3. chronic use of oral or parenteral corticosteroids
4.4. use of drugs prolonging the QT interval (e.g., digoxin, sotalol)
5. Patients with PA who:
5.1. participated in any clinical study within 6 weeks
5.2. suffered a significant blood loss within <2 months
5.3. had a significant illness within <2 weeks
5.4. are pregnant or breastfeeding are unable to follow all study procedures
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 | EUCTR2019-000919-85-NL |
| ClinicalTrials.gov | NCT04007406 |
| CCMO | NL71652.091.19 |