Primary: To determine the individual response to the SGTL2 inhibitor dapagliflozin in urine albumin-to-creatinine ratio (UACR) Secondary:- To determine the individual response to the SGLT2 inhibitor dapagliflozin in: - Systolic blood pressure - Body…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Diabetic complications
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study goal is to assess the change in first morning urinary
albumin-to-creatinine ratio from start to end of treatment.
Secondary outcome
Secondary study goal is to assess changes from baseline in systolic blood
pressure, body weight, eGFR and fasting plasma glucose.
Background summary
Persistent increased albuminuria is a strong risk marker for progressive kidney
disease and cardiovascular disease in patients with or without diabetes. The
degree of albuminuria reduction in the first months of treatment with
pharmacological or dietary intervention correlates with the degree of long-term
(3 to 4 years) renal or cardiovascular protection. Despite the various
available treatments to decrease urinary albumin excretion, residual
albuminuria persists in many patients. The high residual albuminuria in a
proportion of patients is at least in part explained by suboptimal response to
the current treatments (i.e., ACE inhibitor or Angiotensin Receptor Blockers).
Dapagliflozin is a sodium-glucose transport inhibitor and inhibits the
reabsorption of glucose in the proximal tubule. This leads to a decrease in
fasting plasma glucose and HbA1c in patients with type 2 diabetes. In addition,
dapagliflozin administration causes a decrease in blood pressure and body
weight and an increase in hematocrit suggestive of a diuretic effect. Previous
studies have also demonstrated the albuminuria lowering effects of
dapagliflozin in patients with type 2 diabetes mellitus.
Although dapagliflozin markedly slows progression of kidney function decline
(and reduces cardiovascular outcomes) on a population level, randomized
parallel group trials have suggested a marked variation in the response to
dapagliflozin between individual patients. By design, randomized parallel group
placebo-controlled clinical trials test the efficacy of new interventions on a
population level but do not assess the efficacy of a drug for the individual.
Although there is variation in response between patients, parallel group trial
does not allow conclusions whether this variation is a true variation in drug
response, or measurement or temporal random variation. We therefore propose a
cross-over trial with repeated administration (i.e., a series of N=1 trials) to
ascertain the individual drug response. This design specifically allows for
assessment of drug efficacy and safety at an individual level.
Study objective
Primary: To determine the individual response to the SGTL2 inhibitor
dapagliflozin in urine albumin-to-creatinine ratio (UACR)
Secondary:
- To determine the individual response to the SGLT2 inhibitor dapagliflozin in:
- Systolic blood pressure
- Body weight and
- eGFR
- Fasting plasma glucose
Study design
Randomized placebo-controlled double-blind cross-over N=1 trial. Eligible
participants will be invited for screening. After a screening visit, eligible
patients will be randomly assigned to a cross-over study consisting of two
periods of 1-week treatment with dapagliflozin and two periods of 1-week
treatment with placebo in random order with a 1-week wash-out period between
every treatment period to avoid cross-over effects. Based on a prior study
where patients were exposed to dapagliflozin 10 mg, effects of dapagliflozin on
UACR, blood pressure, body weight, eGFR and plasma glucose were fully present
after 1 week and returned to baseline 4 days after drug discontinuation. Hence,
a 1-week treatment followed by 1 week wash-out is considered sufficient to
detect treatment effects.
Intervention
Dapagliflozin tablets and matching placebos will be purchased and provided by
AstraZeneca. Patients take 10 mg dapagliflozin or matching placebo once daily
in the morning according to a randomized treatment scheme. At the randomization
visit, study medication will be dispensed in standard medicine bottles with a
cap that allows real-time monitoring of adherence. Patients receive four
numbered bottles with seven tablets in each bottle, according to their
randomized treatment schema.
Study burden and risks
The efficacy and safety of dapagliflozin is established in multiple parallel
randomized controlled trials involving more than 25,000 patients with type 2
diabetes. Urinary tract infections and genital infections are the most
frequently reported side effects. Dapagliflozin reduces body weight unlike
sulfonylurea derivatives and insulin.
Participants visit the outpatient clinic at three occasions (i.e., a screening
visit, a randomization visit and end of study visit) and have to record body
weight and blood pressure at home and collect blood and urine at home.
Blood pressure and body weight are measured at home by the participants using
ambulant devices (Withings BPM Connect and Withings Body+, respectively).
Patients measure their blood pressure and body weight once daily on 28 and 40
days in total, respectively. Capillary blood will be sampled at home by
participants using a BD Microtainer® Contact-Activated Lancet (once daily on 22
days in total). Blood is collected with the Hem-Col® device, which is designed
to collect capillary blood drawn with a finger prick. In order to make patients
comfortable with the blood collection procedures, they first collect a
capillary blood sample at the study site during the randomization visit under
supervision of trained lab technicians. A venous blood sample will also be
taken during the randomization visit in order to compare the clinical chemistry
assessments in capillary blood with those measured in venous blood samples
(NL70447.100.19). Participants will be asked to draw blood samples at home by a
finger prick and send the samples to the laboratory. Participants will collect
first morning void urine samples through the PeeSpot® device (once daily on 40
days in total) which allows for decentralized urine collection in a small tube.
The urine tubes and blood samples will be sent by regular mail to the
laboratory. No other invasive measurements will be executed.
The advantage of an N=1 study is that efficacy of the intervention is vetted
for the actual participant. Dapagliflozin is currently marketed in the
Netherlands and recommended in patients with type 2 diabetes mellitus and
eGFR>45 mL/min/1.73m2. Patients who show a satisfactory response to
dapagliflozin and whose characteristics fulfull the criteria according to which
dapagliflozin can be prescribed in clinical practice are offered to receive
dapagliflozin after the study. It is expected that the indication for
dapagliflozin will be broadened to patients with eGFR 25-45 mL/min/1.73m2 in
the near future. If this occurs, these patients can also be treated on-label in
practice.
The expected time investment for patients is 20 hours, including measurements
at home. Patients receive restitution of travel costs to visit the outpatient
clinic for the screening, randomization and end of study visit. Patients
receive no priority in treatment of other diseases in the clinic during this
study. Participation in this study is on a free-will base. Patients can keep
the blood pressure device and body weight scale at the end of the study.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
- Age >= 18 years
- Diagnosis of type 2 diabetes mellitus
- Urinary albumin-to-creatinine ratio >20 mg/g (2.26 mg/mmol)
- eGFR >30 ml/min/1.73m2
- Willing to sign informed consent
Exclusion criteria
- Diagnosis of type 1 diabetes
- Prior treatment with SGLT2 inhibitor in the four weeks prior to randomization
- History of severe hypersensitivity or contraindications to dapagliflozin
- Unable to monitor blood pressure / body weight or handle digital technologies
- History of non-adherence to medical regimens or unwillingness to comply with
the study protocol
- Participation in any clinical investigation within 3 months prior to initial
dosing
- Unstable or rapidly progressing renal disease
- Severe hepatic impairment (Child-Pugh class C) as determined by the treating
physician.
- Active malignancy
- Any medication, surgical or medical condition which might significantly alter
the absorption, distribution, metabolism, or excretion of medications
including, but not limited to any of the following:
o History of active inflammatory bowel disease, within the last six months.
o Major gastrointestinal tract surgery as decided by the treating physician
o Pancreatitis within the last six months.
o Evidence of serious hepatic disease as determined by the treating physician
o Evidence of urinary obstruction or difficulty in voiding at screening.
- Confirmed lactose intolerance demonstrated with a lactose intolerance test.
- Donation or loss of 400 mL of blood within 8 weeks prior to initial dosing
- History of drug or alcohol abuse within the 12 months prior to dosing, or
evidence of such abuse as indicated by the laboratory assays conducted during
the screening
- Any surgical or medical condition, which in the opinion of the investigator,
may place the patient at higher risk from his/her participation in the study,
or is likely to prevent the patient from complying with the requirements of the
study or completing the study.
- Current pregnancy or breast feeding / attempting to conceive.
- Women of childbearing potential (WOCBP):
o WOCBP who are unwilling or unable to use an acceptable method of
contraception to avoid pregnancy throughout the study and for up to 4 weeks
after the last dose of study drug in such a manner the risk of pregnancy is
minimized.
o WOCBP must have a negative serum or urine pregnancy test result (minimum
sensitivity 25 IU/L or equivalent of HCG) within 0 to 72 hours before the first
dose of study drug.
WOCBP comprises women who have experienced menarche and who have not undergone
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or who are not post-menopausal (see definition below).
The following women are WOCBP:
- Women using the following methods to prevent pregnancy: oral contraceptives,
other hormonal contraceptives (vaginal products, skin patches, or implanted or
injectable products), or mechanical products such as intrauterine devices or
barrier methods (diaphragm, condoms, spermicides).
- Women who are practicing abstinence.
- Women who have a partner who is sterile (e.g. due to vasectomy).
Post-menopause is defined as:
- Women who have had amenorrhea for >12 consecutive months (without another
cause) and who have a documented serum follicle-stimulating hormone (FSH) level
>35 mIU/mL.
- Women who have irregular menstrual periods and a documented serum FSH level
>35 mIU/mL.
- Women who are taking hormone replacement therapy (HRT).
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-004929-23-NL |
| CCMO | NL75914.042.20 |
| Other | NL9060 |
| OMON | NL-OMON26308 |