| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Distal renal tubular acidosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Genetic disease resulting in too low blood pH |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| 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 | 10038535 |
| E.1.2 | Term | Renal tubular acidosis |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the long term safety and tolerability of ADV7103 in subjects with primary distal renal tubular acidosis (dRTA). |
|
| E.2.2 | Secondary objectives of the trial |
•Evaluate the long term efficacy of ADV7103 in maintaining targeted serum bicarbonate levels and preventing metabolic acidosis in dRTA subjects;
•Evaluate the long term efficacy of ADV7103 in maintaining targeted serum potassium levels in dRTA subjects;
•Evaluate the effects of ADV7103 on hypocitraturia;
•Evaluate the effects of ADV7103 on hypercalciuria. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for subjects who did not participate in Study B23CS:
1. Female or male subjects ≤ 65 years of age at time of consent with the following stipulations:
a. Subjects ≥ 6 months of age must reside in Europe
b. Subjects < 6 months of age may reside in the United States, Canada, or Europe and must be clinically stable as determined in consultation with the Sponsor and Medical Monitor;
2. Subjects < 6 months of age must be able to swallow (not suck) solid food without difficulty in the judgment of the Investigator;
3. Subject presents with a previous diagnosis of primary dRTA: the diagnosis duration must be reviewed by the Medical Monitor for subjects < 6 months of age, at least 4 months duration for subjects > 6 months and < 12 years of age, and at least one year for subjects ≥ 12 years of age, based on documented history of non-anion gap, hyperchloremic, hypokalemic metabolic acidosis;
4. Subject ≥ 6 months of age requires ≥ 0.9 mEq/kg/day of alkali therapy to maintain serum bicarbonate levels above the LLN for the laboratory providing results (subject < 6 months of age may be started on ADV7103 dose deemed appropriate by Investigator in consultation with Medical Monitor);
5. Urine pH > 5.5 and serum bicarbonate > 18 mEq/L for subjects ≥ 4 years old or > 17 mEq/L for subjects < 4 years old on alkali therapy and potassium supplementation (if indicated) on at least one occasion for each within 6 months prior to the initial study visit (a subject < 6 months old may enter the study solely on the basis of a diagnosis of non anion gap, hyperchloremic, hypokalemic metabolic acidosis after review by the Medical Monitor);
6. European subjects must be included in a social health insurance system and/or in compliance with the recommendations of the national law in force relating to biomedical research;
7. Subject or parent/guardian is willing and able to understand and sign informed consent and willing to comply with protocol instructions; child assent when appropriate; and
8. Female subjects of childbearing potential and non sterilized males must use at least one of the following acceptable birth control methods from informed consent through 7 days after the last dose of study product:
a. Double barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository)
b. Established use of oral, injectable, or implanted hormonal methods of contraception
c. Placement of an intrauterine device or intrauterine system
Abstinence may be used in place of an acceptable contraceptive regimen. Females of childbearing potential are those who have reached the onset of menarche and are not postmenopausal (≥ 1 year without menses prior to the initial study visit)], surgically sterile, or status post hysterectomy (≥ 1 month prior to the initial study visit). Pregnancy testing is not required for premenarchal females who are abstinent. From informed consent through 7 days after the last dose of study product, female subjects of childbearing potential must agree to refrain from egg donation and male subjects of age must agree to refrain from sperm donation.
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|
| E.4 | Principal exclusion criteria |
Exclusion criteria for subjects who did not participate in Study B23CS:
1. Female subject who is pregnant or lactating or has plans for pregnancy during the study;
2. Subject has evidence of proximal tubule dysfunction (eg, hypophosphatemia, low serum uric acid, glycosuria, or amino aciduria) unless the subject is < 6 months of age;
3. Subject presents with another diagnosed condition as a potential etiology for her/his dRTA (eg, systemic lupus erythematosus, Sjogren's syndrome);
4. Subject requires therapy with potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, trimethoprim, drospirenone and other progestins, nephrotoxic antibiotics, penicillins, tacrolimus, or medications known to delay gastric emptying or otherwise interfere with absorption of study product;
5. Subject has evidence of obstructive uropathy or other findings on renal ultrasound expected to require intervention during the course of the study;
6. Subject has any of the following laboratory abnormalities:
a. AST and/or ALT > 1.5x upper limit of normal (ULN)
b. Serum potassium > 5.0 mEq/L or hypokalemia accompanied by clinical symptoms (eg, muscle cramps) or significant ECG changes (eg, T wave depression, U wave elevation)
c. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (according to the modified Schwartz formula for children and Chronic Kidney Disease – Epidemiology Collaboration [CKD-EPI] formula for adults). For subjects 14 to 17 years of age with an eGFR < 60 mL/min/1.73 m2 via the modified Schwartz formula, the eGFR may be recalculated using the pediatric cystatin C equation if there is a cystatin C result less than 120 days old and serum creatinine has not changed by more than 20% over the last
120 days. If cystatin C results are not available, the qualifying eGFR can be calculated by using both the modified Schwartz and CKD EPI methods and averaging these values to obtain the eGFR.
d. Total bilirubin > ULN, except with known Gilbert's disease.
7. Subject has been hospitalized or had outpatient surgery (other than minor skin and dRTA disease-related procedures or ear tube placement) in the past 6 months or is planning surgery in the next 6 months;
8. In the opinion of the Investigator, the subject has a major medical or psychiatric condition (eg, significant cardiac disease, schizophrenia) or an unstable condition (eg, uncontrolled hypertension, asthma, diabetes, hypercholesterolemia, or cardiac disease) that would potentially interfere with the subject safely completing the study;
9. In the opinion of the Investigator, the subject has a history of difficulty taking oral medication and/or conditions that may hamper absorption of the study product (eg, any difficulty of swallowing, malabsorption, delayed gastric emptying, esophageal compression, intestinal obstruction, or other chronic gastrointestinal disease);
10. Self-reported or parent/guardian reported alcohol abuse or drug abuse within the past 12 months;
11. Subject is a solid organ or bone marrow transplant recipient;
12. Subject has a history of malignancy within 5 years prior to the screening visit, except for localized skin or cervical carcinoma; or
13. Subject is known to have an allergy to any ADV7103 constituents.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Number/proportion of subjects presenting with ADV7103 treatment related adverse events (AEs) during the study, by severity grade. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Number/proportion of subjects with serum bicarbonate levels in the normal range for age during ≥ 80% of study encounters (study visits and remote interactions);
• Number/proportion of subjects with serum potassium levels in the normal range for age during ≥ 80% of study encounters (study visits and remote interactions);
• Number/proportion of subjects with a serum potassium level < 3.5 mEq/L;
• Number/proportion of subjects with a serum potassium level < 3.0 mEq/L;
• Mean and change from SOC baseline in serum bicarbonate level (SOC baseline is the initial study visit for Study B23CS nonparticipants and Visit 1 in Study B23CS for participants);
• Number/proportion of subjects with urine citrate (expressed as 24 hour urine citrate excretion when feasible and as urine citrate/creatinine ratio) in the normal, abnormally low, and abnormally high ranges for age;
• Number/proportion of subjects with hypocitraturia;
• Number/proportion of subjects with urine calcium (expressed as 24 hour urine calcium excretion when feasible and as calcium/creatinine urine ratio) in the normal, abnormally low, and abnormally high ranges for age;
• Number/proportion of subjects with hypercalciuria;
• Number/proportios of subjects with a normal, abnormally low, and abnormally high calcium/citrate urine ratio;
• Change from SOC baseline in physical examinations, vital signs, ECG parameters, blood parameters, and urine parameters;
• Number/proportion of subjects with urine pH > 8.5
• Number/proportion of subjects with positive crystalluria
• Number/proportion of subjects adherent to prescribed ADV7103 treatment: less than 50%, at least 50%, at least 75%, at least 90%, and more than 110%, of the time (based ADV7103 accountability data coupled with ADV7103 paper dosing diary data).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Canada |
| Germany |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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