Decentralized N=1 Study: A Feasible Approach to Evaluate Individual Therapy Response to Dapagliflozin. — @HOME  

Diabetes Mellitus, Type 2 Clinical Trial

Official title: Individual Albuminuria Lowering Response to Dapagliflozin in a Decentralized Clinical Trial in Patients With Type 2 Diabetes Mellitus and Elevated Albuminuria

Status Completed

Clinical Trial Summary

Randomized placebo-controlled double-blind cross-over N=1 trial in adult male and female patients with UACR >20 mg/g (2.26 mg/mmol) with type 2 diabetes treated in primary or secondary healthcare.

The goal of this clinical trial is to determine the individual response to the SGLT2 inhibitor dapagliflozin in urine albumin-to-creatinine ratio (UACR). Secondary objectives are to determine the individual response to dapagliflozin in systolic blood pressure, body weight, eGFR, and fasting plasma glucose.

Participants will collect all study data in the comfort of their own environments:

• First-morning void urine samples

• Capillary blood samples

• Blood pressure

• Body weight

Participants will be randomly assigned to a cross-over study consisting of two periods of 1-week treatment with dapagliflozin 10 mg/day 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.

Clinical Trial Description

Rationale:

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. The investigators 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.

Objectives:

• 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, 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.

Study population:

Adult male and female patients with UACR >20 mg/g (2.26 mg/mmol) with type 2 diabetes mellitus treated in primary or secondary healthcare. Subjects will be recruited via general practitioner practices and via the outpatient clinic of the Department of Internal Medicine of the Ziekenhuisgroep Twente, Almelo.

Intervention:

Dapagliflozin 10 mg/day

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

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 second 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). Participants 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 second visit under supervision of trained lab technicians. A venous blood sample will also be taken during the second 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 fulfill 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 participants is 20 hours, including measurements at home. Participants receive restitution of travel costs to visit the outpatient clinic for the screening, randomization and end of study visit. Participants receive no priority in treatment of other diseases in the clinic during this study. Participation in this study is on a free-will base. Participants can keep the body weight scale and blood pressure device at the end of the study. ;

Related Conditions & MeSH terms

• Albuminuria
• Chronic Kidney Disease Due to Type 2 Diabetes Mellitus
• Chronic Kidney Diseases
• CKD
• Diabetes
• Diabetes Complications
• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Kidney Diseases
• Proteinuria
• Renal Insufficiency, Chronic

• NCT number: NCT06374043
• Study type: Interventional
• Source: University Medical Center Groningen
• Status: Completed
• Phase: Phase 4
• Start date: May 11, 2021
• Completion date: September 13, 2022