Patients with dRTA that completed a previous phase II/III study22 with ADV7103 were included in a 2-year extension study. It was a multicenter, single-arm, open-label trial (EudraCT 2013-003828-36, registered in September 2013), aiming to assess efficacy, safety, and tolerability, of treatment with ADV7103 in paediatric and adult patients.23 The study was approved by regional independent ethics committees (i.e. the Ethics Committee CPP Sud Est II in France, the Ethics Committee of the Bratislava Children's Hospital in Slovakia and the Ethics Committee of the Clinical Centre Nis in Serbia) and national regulatory health authorities (i.e. French National Agency for the Safety of Medicines and Health Products (ANSM), Slovakia State Institute for Drug Control (SUKL) and Medicines and Medical Devices Agency Serbia (ALIMS), and conducted in accordance with Good Clinical Practice and the Declaration of Helsinki.

A total of thirty patients (24 paediatric and 6 adults) (Table 1), from 12 different centres in France, Serbia and Slovakia were included. They continued treatment with ADV7103 given twice daily at the optimal doses determined during the phase II/III study (the dose was further adapted if required).

Exclusion criteria were hyperkalaemia (plasma potassium>5.0mmol/L), kidney function impairment (eGFR <45mL/min/1.73m2), or any other condition that could be negatively affected by the study medication or that could affect the concomitant treatment with potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, or tacrolimus. Written informed consent was obtained from all adult patients, and from the parents or legal guardians of all children. Patients were evaluated at baseline (last visit of the phase II/III trial) and at 3, 6, 12, 18 and 24 months of treatment.

Bone mineral density (BMD, g/cm2) was measured at baseline and after the 24-month treatment period in three skeletal regions (spine, hip and whole body) using dual-energy X-ray absorptiometry (DXA). Measurements for each patient were performed with the DXA tools available at their local hospital. Values of z-score≤−2.0 were considered below the normal range, according to the International Society for Clinical Densitometry (ISCD) recommendations.24

Height (cm), weight (kg) and BMI were measured at each study visit and z-scores were determined considering age and sex, according to WHO standards for paediatric patients<5 years25 and from 5 to 19 years old.26 Weight standards for paediatric patients 11–19 years old were obtained from the data provided by the French Auxology Group.27

Stunting and failure to thrive were considered, for height- and for weight-for-age z-scores≤−2.0. We determined the number of patients with an increase of height- or weight-for-age z-scores>0.5 units from baseline to the end of the 24-month treatment.

Growth velocity was calculated as the difference between height measurements performed during two consecutive visits and expressed as cm/6 month.28,29

Genetic target stature (GTS) was calculated according to the American College of Medical Genetics practice guideline.30 The difference between GTS and actual height was estimated in adult patients at baseline and after 24 months; short stature was considered if the difference was>10cm in men and >9cm in women.31

During each study visit, blood samples were obtained, before the first morning dose of ADV7103. Serum bicarbonate, phosphate, calcium, and 25-hydroxy-vitamin D were determined by local laboratories. The serum concentration of bone alkaline phosphatases (bALP), 1,25-dihydroxy-vitamin D, and parathyroid hormone (PTH) were determined by immunoluminometry by a central laboratory. Normal values for bALP were adjusted to age and sex. Urine samples were also collected in the morning, to calculate the ratios calcium/creatinine (UCa/UCr), citrate/creatinine (UCi/UCr), calcium/citrate (UCa/UCi) and phosphate/creatinine (UP/UCr). These measurements were also performed by local laboratories.23 See supplemental document for all normal values.

The occurrence of adverse events (AEs) was recorded throughout the study, including abnormal values of laboratory data, electrocardiogram (ECG) findings (12-lead resting ECG standard including heart rate, PR, QRS, and QT intervals), vital signs (blood pressure, heart rate, and respiratory rate), and physical examinations (articular system, bone system, general appearance, and muscular system); the severity of the adverse events was recorded.

The adherence to the treatment was assessed in all patients based on the returned empty boxes. This was done at each study visit up to the completion of the 24-month period. Four categories of adherence were considered: excellent (>90%), good (75-90%), average (50-74%), and poor (<50%). In the absence of returned boxes, the investigators classed the patient in one of the four categories on the basis of interviews and laboratory results.

Clinical signs, such as diffuse bone and joint pain, myalgia, muscle weakness, abnormal posture, and abnormal height were registered throughout the follow up.

Descriptive statistics were performed to obtain the mean and standard deviation (SD) or median (range), as well as changes from baseline and 95% confidence intervals, at the different time points in all patients and in groups separated by age.

Comparison of mean values of the parameters evaluated at the different time points and between age groups was performed by non-parametric methods (Kruskal–Wallis and Mann–Whitney U tests). Comparison of the densitometric parameters was performed using Student's t-test. The groups have been considered as random samples to avoid the missing data effect.

Pearson's correlation coefficient or the Spearman's Rho coefficient were used to assess the potential correlations between age, growth velocity and other parameters, including densitometry, including data from the evaluations at baseline and at the 24-month visit.

All the tests were two-sided, considering the differences as statistically significant when p≤0.05. Statistical analyses were performed using IBM SPSS Statistics, version 27.0.0.0.

Changes in BMD z-scores after 24 months of treatment are shown in Table 2. The overall mean spine z-score significantly increased from -1.1at baseline to −0.8 at 24 months (Student's t-test; p=0.024), while no significant change was observed in hip and whole-body z-scores.

Correlations were found when evaluating the relationship between BMD z-scores and blood and urine parameters, including all data available from the evaluations at baseline and at the 24-month visit. In children, whole-body BMD z-scores (n=10) showed a statistically significant direct (positive) correlation with the UCi/UCr ratio (rS=0.745, p=0.013). In adolescents, the whole-body densitometry z-scores (n=12) showed a statistically significant indirect (negative) correlation with UCa/UCr ratio (rS=−0.585, p=0.046). In the case of adults (Fig. 1), spine (n=10) and whole-body (n=6) BMD z-scores, showed statistically significant direct correlation with plasma bicarbonate levels (rS=0.817, p=0.004 and rS=0.971, p=0.001, respectively).

Fig. 1.

In adults, spine and whole-body densitometry z-scores showed statistically significant direct correlation with plasma bicarbonate levels (rS=0.82 and rS=0.97, respectively, p<0.005).

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Between the first and the third month of the study, 5/24 (21%) children presented height velocity values below the 3rd centile and by the end of the study all patients were above the 3rd centile and 18 of them (75%) were above the 25th centile. The mean growth velocity in the overall paediatric population (Table 3) did not show statistically significant changes throughout the study (ANOVA p=0.522).

At baseline most children presented z-scores within the ±2SD range for weight, height and BMI. After completion of 24 months of study, the change in z-score for height was 0.2±0.5; for weight the change was also 0.2±0.5 (Table 4). Among children with available data height and weight-for-age z-scores increased>0.5 units in 4 (18%) and 8 (36%), respectively. Fig. 2 shows the evolution of mean height and weight z-scores throughout the study. Particularly interesting was the positive evolution of growth of a girl (4.5 years old at study entry), who presented stunting and failure to thrive (z-scores<−2) at baseline. Her height and weight-to-age z-scores were both>−2 by the end of the study (they increased by 1.8 and 0.8 units, respectively).

Fig. 2.

Evolution of mean (SEM) height and weight-for-age z-scores in paediatric patients.

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Considering the 5 adults with available data (19–21 years old) mean height increased by 1.8±0.8cm after the 2 years of treatment (Table 5). While at baseline their mean height was 0.9cm below the GTS, they caught up and exceeded GTS by 1.1cm at the end of the treatment.

After the phase II/III the serum bicarbonate was normal in 63% of patients and it remained normal in most patients (69 to 86%) throughout the 24 months of treatment. At 24 months, overall mean±SD plasma bicarbonate levels were 22.8±2.9mmol/L. Clinically significant metabolic acidosis was reported in one adult patient presenting bicarbonate levels of 19.0mmol/L at the two last visits. With the exception of two cases of occasional hypercalciuria, the UCa/UCr ratios were normal throughout the study, while 9 to 17 patients presented low UCi/UCr levels at the different visits. Approximately half of the patients presented UCa/UCi excretion ratios below the threshold considered for an increased risk of lithogenesis throughout the study.

PTH and bALP plasma levels were available in 15 patients at baseline and in 24 at the end of the study. Mean (95% CI) PTH was 15.6 (11.1, 20.2) ng/L at baseline and 22.6 (17.4, 27.8) ng/L after 24 months of treatment. There were no significant changes in PTH throughout the study (Kruskal–Wallis p=0.267).

Mean (95% CI) bALP was 57.5 (41.4, 73.6) μg/L at baseline and 53.5 (40.0, 67.0) μg/L after 24 months of treatment without significant modifications observed throughout the study (Kruskal-Wallis p=0.786).

No significant changes in 25-hydroxyvitamin D and 1.25-dihydroxyvitamin D were observed throughout the study (Kruskal–Wallis p=0.349 and 0.131, respectively).

Mean±SD 25-hydroxyvitamin D was 51.5±33.7nmol/L at baseline (n=10) and 58.9±20.8nmol/L at the 24-month visit (n=21). The mean±SD serum level of 1,25-dihydroxyvitamin D was 153±48pmol/L at baseline (n=15) and 135±30pmol/L at the end of the study (n=25).

Blood levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were normal in 60% and 80% of the patients at baseline and in 43% and 100% of the patients after 24 months, respectively. Clinically significant low levels of 25-hydroxyvitamin D were measured at different time points in six paediatric patients. Occasional vitamin D supplementation was given to 60% of patients.

A total of 104 adverse events in 27 patients were reported, among which only 9 in 5 patients were confirmed treatment related: three cases of diarrhoea affecting one patient, two cases of abdominal pain in two children and single events of dyspepsia, upper abdominal pain, gastrointestinal disorder and gastrointestinal pain. They were all of mild or moderate severity and no discontinuation of treatment was needed.22